International Journal of Molecular Sciences

Editorial

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3 pages, 151 KiB

Open AccessEditorial

Special Issue: “New Trends in Diabetes, Hypertension, and Cardiovascular Diseases”

by Yutang Wang and Dianna J. Magliano

Int. J. Mol. Sci. 2024, 25(5), 2711; https://doi.org/10.3390/ijms25052711 - 27 Feb 2024

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Abstract

Cardiovascular disease (CVD) encompasses a range of disorders affecting the heart and blood vessels, including coronary heart disease and cerebrovascular disease [...] Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

Research

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13 pages, 3727 KiB

Open AccessArticle

Effect of Hydralazine on Angiotensin II-Induced Abdominal Aortic Aneurysm in Apolipoprotein E-Deficient Mice

by Yutang Wang, Owen Sargisson, Dinh Tam Nguyen, Ketura Parker, Stephan J. R. Pyke, Ahmed Alramahi, Liam Thihlum, Yan Fang, Morgan E. Wallace, Stuart P. Berzins, Ernesto Oqueli, Dianna J. Magliano and Jonathan Golledge

Int. J. Mol. Sci. 2023, 24(21), 15955; https://doi.org/10.3390/ijms242115955 - 3 Nov 2023

Cited by 3 | Viewed by 2259

Abstract

The rupture of an abdominal aortic aneurysm (AAA) causes about 200,000 deaths worldwide each year. However, there are currently no effective drug therapies to prevent AAA formation or, when present, to decrease progression and rupture, highlighting an urgent need for more research in [...] Read more.

The rupture of an abdominal aortic aneurysm (AAA) causes about 200,000 deaths worldwide each year. However, there are currently no effective drug therapies to prevent AAA formation or, when present, to decrease progression and rupture, highlighting an urgent need for more research in this field. Increased vascular inflammation and enhanced apoptosis of vascular smooth muscle cells (VSMCs) are implicated in AAA formation. Here, we investigated whether hydralazine, which has anti-inflammatory and anti-apoptotic properties, inhibited AAA formation and pathological hallmarks. In cultured VSMCs, hydralazine (100 μM) inhibited the increase in inflammatory gene expression and apoptosis induced by acrolein and hydrogen peroxide, two oxidants that may play a role in AAA pathogenesis. The anti-apoptotic effect of hydralazine was associated with a decrease in caspase 8 gene expression. In a mouse model of AAA induced by subcutaneous angiotensin II infusion (1 µg/kg body weight/min) for 28 days in apolipoprotein E-deficient mice, hydralazine treatment (24 mg/kg/day) significantly decreased AAA incidence from 80% to 20% and suprarenal aortic diameter by 32% from 2.26 mm to 1.53 mm. Hydralazine treatment also significantly increased the survival rate from 60% to 100%. In conclusion, hydralazine inhibited AAA formation and rupture in a mouse model, which was associated with its anti-inflammatory and anti-apoptotic properties. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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12 pages, 2738 KiB

Open AccessArticle

Tumor Growth Ameliorates Cardiac Dysfunction and Suppresses Fibrosis in a Mouse Model for Duchenne Muscular Dystrophy

by Laris Achlaug, Lama Awwad, Irina Langier Goncalves, Tomer Goldenberg and Ami Aronheim

Int. J. Mol. Sci. 2023, 24(16), 12595; https://doi.org/10.3390/ijms241612595 - 9 Aug 2023

Cited by 4 | Viewed by 1675

Abstract

The interplay between heart failure and cancer represents a double-edged sword. Whereas cardiac remodeling promotes cancer progression, tumor growth suppresses cardiac hypertrophy and reduces fibrosis deposition. Whether these two opposing interactions are connected awaits to be determined. In addition, it is not known [...] Read more.

The interplay between heart failure and cancer represents a double-edged sword. Whereas cardiac remodeling promotes cancer progression, tumor growth suppresses cardiac hypertrophy and reduces fibrosis deposition. Whether these two opposing interactions are connected awaits to be determined. In addition, it is not known whether cancer affects solely the heart, or if other organs are affected as well. To explore the dual interaction between heart failure and cancer, we studied the human genetic disease Duchenne Muscular Dystrophy (DMD) using the MDX mouse model. We analyzed fibrosis and cardiac function as well as molecular parameters by multiple methods in the heart, diaphragm, lungs, skeletal muscles, and tumors derived from MDX and control mice. Surprisingly, cardiac dysfunction in MDX mice failed to promote murine cancer cell growth. In contrast, tumor-bearing MDX mice displayed reduced fibrosis in the heart and skeletal and diaphragm muscles, resulting in improved cardiac function. The latter is at least partially mediated via M2 macrophage recruitment to the heart and diaphragm muscles. Collectively, our data support the notion that the effect of heart failure on tumor promotion is independent of the improved cardiac function in tumor-bearing mice. Reduced fibrosis in tumor-bearing MDX mice stems from the suppression of new fibrosis synthesis and the removal of existing fibrosis. These findings offer potential therapeutic strategies for DMD patients, fibrotic diseases, and cardiac dysfunction. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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17 pages, 4140 KiB

Open AccessArticle

Augmentation of Cathepsin Isoforms in Diabetic db/db Mouse Kidneys Is Associated with an Increase in Renal MARCKS Expression and Proteolysis

by Mohammed F. Gholam, Niharika Bala, Yunus E. Dogan and Abdel A. Alli

Int. J. Mol. Sci. 2023, 24(15), 12484; https://doi.org/10.3390/ijms241512484 - 5 Aug 2023

Cited by 2 | Viewed by 1517

Abstract

The expression of the myristoylated alanine-rich C-kinase substrate (MARCKS) family of proteins in the kidneys plays an important role in the regulation of the renal epithelial sodium channel (ENaC) and hence overall blood pressure regulation. The function of MARCKS is regulated by post-translational [...] Read more.

The expression of the myristoylated alanine-rich C-kinase substrate (MARCKS) family of proteins in the kidneys plays an important role in the regulation of the renal epithelial sodium channel (ENaC) and hence overall blood pressure regulation. The function of MARCKS is regulated by post-translational modifications including myristoylation, phosphorylation, and proteolysis. Proteases known to cleave both ENaC and MARCKS have been shown to contribute to the development of high blood pressure, or hypertension. Here, we investigated protein expression and proteolysis of MARCKS, protein expression of multiple protein kinase C (PKC) isoforms, and protein expression and activity of several different proteases in the kidneys of diabetic db/db mice compared to wild-type littermate mice. In addition, MARCKS protein expression was assessed in cultured mouse cortical collecting duct (mpkCCD) cells treated with normal glucose and high glucose concentrations. Western blot and densitometric analysis showed less abundance of the unprocessed form of MARCKS and increased expression of a proteolytically cleaved form of MARCKS in the kidneys of diabetic db/db mice compared to wild-type mice. The protein expression levels of PKC delta and PKC epsilon were increased, while cathepsin B, cathepsin S, and cathepsin D were augmented in diabetic db/db kidneys compared to those of wild-type mice. An increase in the cleaved form of MARCKS was observed in mpkCCD cells cultured in high glucose compared to normal glucose concentrations. Taken together, these results suggest that high glucose may contribute to an increase in the proteolysis of renal MARCKS, while the upregulation of the cathepsin proteolytic pathway positively correlates with increased proteolysis of MARCKS in diabetic kidneys, where PKC expression is augmented. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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12 pages, 2137 KiB

Open AccessArticle

Prognostic Significance of Activated Monocytes in Patients with ST-Elevation Myocardial Infarction

by Mohamed Abo-Aly, Elica Shokri, Lakshman Chelvarajan, Wadea M. Tarhuni, Himi Tripathi and Ahmed Abdel-Latif

Int. J. Mol. Sci. 2023, 24(14), 11342; https://doi.org/10.3390/ijms241411342 - 12 Jul 2023

Cited by 3 | Viewed by 1461

Abstract

Circulating monocytes have different subsets, including classical (CD14++CD16−), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++), which play different roles in cardiovascular physiology and disease progression. The predictive value of each subset for adverse clinical outcomes in patients with coronary artery disease is not fully understood. [...] Read more.

Circulating monocytes have different subsets, including classical (CD14++CD16−), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++), which play different roles in cardiovascular physiology and disease progression. The predictive value of each subset for adverse clinical outcomes in patients with coronary artery disease is not fully understood. We sought to evaluate the prognostic efficacy of each monocyte subset in patients with ST-elevation myocardial infarction (STEMI). We recruited 100 patients with STEMI who underwent primary percutaneous coronary intervention (PCI). Blood samples were collected at the time of presentation to the hospital (within 6 h from onset of symptoms, baseline (BL)) and then at 3, 6, 12, and 24 h after presentation. Monocytes were defined as CD45+/HLA-DR+ and then subdivided based on the expression of CD14, CD16, CCR2, CD11b, and CD42. The primary endpoint was a composite of all-cause death, hospitalization for heart failure, stent thrombosis, in-stent restenosis, and recurrent myocardial infarction. Univariate and multivariate Cox proportional hazards models, including baseline comorbidities, were performed. The mean age of our cohort was 58.9 years and 25% of our patients were females. Patients with high levels (above the median) of CD14+CD16++ monocytes showed an increased risk for the primary endpoint in comparison to patients with low levels; adjusted hazard ratio (aHR) for CD14+/CD16++ cells was 4.3 (95% confidence interval (95% CI) 1.2–14.8, p = 0.02), for CD14+/CD16++/CCR2+ cells was 3.82 (95% CI 1.06–13.7, p = 0.04), for CD14+/CD16++/CD42b+ cells was 3.37 (95% CI 1.07–10.6, p = 0.03), for CD14+/CD16++/CD11b+ was 5.17 (95% CI 1.4–18.0, p = 0.009), and for CD14+ HLA-DR+ was 7.5 (95% CI 2.0–28.5, p = 0.002). CD14++CD16−, CD14++CD16+, and their CD11b+, CCR2+, and CD42b+ aggregates were not significantly predictive for our composite endpoint. Our study shows that CD14+ CD16++ monocytes and their subsets expressing CCR2, CD42, and CD11b could be important predictors of clinical outcomes in patients with STEMI. Further studies with a larger sample size and different coronary artery disease phenotypes are needed to verify the findings. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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18 pages, 1858 KiB

Open AccessArticle

Age-Dependent Changes in the Relationships between Traits Associated with the Pathogenesis of Stress-Sensitive Hypertension in ISIAH Rats

by Dmitry Yu. Oshchepkov, Yulia V. Makovka, Mikhail P. Ponomarenko, Olga E. Redina and Arcady L. Markel

Int. J. Mol. Sci. 2023, 24(13), 10984; https://doi.org/10.3390/ijms241310984 - 1 Jul 2023

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Abstract

Hypertension is one of the most significant risk factors for many cardiovascular diseases. At different stages of hypertension development, various pathophysiological processes can play a key role in the manifestation of the hypertensive phenotype and of comorbid conditions. Accordingly, it is thought that [...] Read more.

Hypertension is one of the most significant risk factors for many cardiovascular diseases. At different stages of hypertension development, various pathophysiological processes can play a key role in the manifestation of the hypertensive phenotype and of comorbid conditions. Accordingly, it is thought that when diagnosing and choosing a strategy for treating hypertension, it is necessary to take into account age, the stage of disorder development, comorbidities, and effects of emotional–psychosocial factors. Nonetheless, such an approach to choosing a treatment strategy is hampered by incomplete knowledge about details of age-related associations between the numerous features that may contribute to the manifestation of the hypertensive phenotype. Here, we used two groups of male F₂(ISIAHxWAG) hybrids of different ages, obtained by crossing hypertensive ISIAH rats (simulating stress-sensitive arterial hypertension) and normotensive WAG rats. By principal component analysis, the relationships among 21 morphological, physiological, and behavioral traits were examined. It was shown that the development of stress-sensitive hypertension in ISIAH rats is accompanied not only by an age-dependent (FDR < 5%) persistent increase in basal blood pressure but also by a decrease in the response to stress and by an increase in anxiety. The plasma corticosterone concentration at rest and its increase during short-term restraint stress in a group of young rats did not have a straightforward relationship with the other analyzed traits. Nonetheless, in older animals, such associations were found. Thus, the study revealed age-dependent relationships between the key features that determine hypertension manifestation in ISIAH rats. Our results may be useful for designing therapeutic strategies against stress-sensitive hypertension, taking into account the patients’ age. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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14 pages, 2448 KiB

Open AccessArticle

Preliminary Study on the Effect of a Night Shift on Blood Pressure and Clock Gene Expression

by Barbara Toffoli, Federica Tonon, Fabiola Giudici, Tommaso Ferretti, Elena Ghirigato, Matilde Contessa, Morena Francica, Riccardo Candido, Massimo Puato, Andrea Grillo, Bruno Fabris and Stella Bernardi

Int. J. Mol. Sci. 2023, 24(11), 9309; https://doi.org/10.3390/ijms24119309 - 26 May 2023

Cited by 8 | Viewed by 4318

Abstract

Night shift work has been found to be associated with a higher risk of cardiovascular and cerebrovascular disease. One of the underlying mechanisms seems to be that shift work promotes hypertension, but results have been variable. This cross-sectional study was carried out in [...] Read more.

Night shift work has been found to be associated with a higher risk of cardiovascular and cerebrovascular disease. One of the underlying mechanisms seems to be that shift work promotes hypertension, but results have been variable. This cross-sectional study was carried out in a group of internists with the aim of performing a paired analysis of 24 h blood pressure in the same physicians working a day shift and then a night shift, and a paired analysis of clock gene expression after a night of rest and a night of work. Each participant wore an ambulatory blood pressure monitor (ABPM) twice. The first time was for a 24 h period that included a 12 h day shift (08.00–20.00) and a night of rest. The second time was for a 30 h period that included a day of rest, a night shift (20.00–08.00), and a subsequent period of rest (08.00–14.00). Subjects underwent fasting blood sampling twice: after the night of rest and after the night shift. Night shift work significantly increased night systolic blood pressure (SBP), night diastolic blood pressure (DBP), and heart rate (HR) and decreased their respective nocturnal decline. Clock gene expression increased after the night shift. There was a direct association between night blood pressure and clock gene expression. Night shifts lead to an increase in blood pressure, non-dipping status, and circadian rhythm misalignment. Blood pressure is associated with clock genes and circadian rhythm misalignement. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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21 pages, 1760 KiB

Open AccessArticle

SERPINE1 mRNA Binding Protein 1 Is Associated with Ischemic Stroke Risk: A Comprehensive Molecular–Genetic and Bioinformatics Analysis of SERBP1 SNPs

by Irina Shilenok, Ksenia Kobzeva, Tatiana Stetskaya, Maxim Freidin, Maria Soldatova, Alexey Deykin, Vladislav Soldatov, Mikhail Churnosov, Alexey Polonikov and Olga Bushueva

Int. J. Mol. Sci. 2023, 24(10), 8716; https://doi.org/10.3390/ijms24108716 - 13 May 2023

Cited by 6 | Viewed by 2556

Abstract

The SERBP1 gene is a well-known regulator of SERPINE1 mRNA stability and progesterone signaling. However, the chaperone-like properties of SERBP1 have recently been discovered. The present pilot study investigated whether SERBP1 SNPs are associated with the risk and clinical manifestations of ischemic stroke [...] Read more.

The SERBP1 gene is a well-known regulator of SERPINE1 mRNA stability and progesterone signaling. However, the chaperone-like properties of SERBP1 have recently been discovered. The present pilot study investigated whether SERBP1 SNPs are associated with the risk and clinical manifestations of ischemic stroke (IS). DNA samples from 2060 unrelated Russian subjects (869 IS patients and 1191 healthy controls) were genotyped for 5 common SNPs—rs4655707, rs1058074, rs12561767, rs12566098, and rs6702742 SERBP1—using probe-based PCR. The association of SNP rs12566098 with an increased risk of IS (risk allele C; p = 0.001) was observed regardless of gender or physical activity level and was modified by smoking, fruit and vegetable intake, and body mass index. SNP rs1058074 (risk allele C) was associated with an increased risk of IS exclusively in women (p = 0.02), non-smokers (p = 0.003), patients with low physical activity (p = 0.04), patients with low fruit and vegetable consumption (p = 0.04), and BMI ≥25 (p = 0.007). SNPs rs1058074 (p = 0.04), rs12561767 (p = 0.01), rs12566098 (p = 0.02), rs6702742 (p = 0.036), and rs4655707 (p = 0.04) were associated with shortening of activated partial thromboplastin time. Thus, SERBP1 SNPs represent novel genetic markers of IS. Further studies are required to confirm the relationship between SERBP1 polymorphism and IS risk. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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27 pages, 4754 KiB

Open AccessArticle

Sex-Specific Features of the Correlation between GWAS-Noticeable Polymorphisms and Hypertension in Europeans of Russia

by Tatiana Ivanova, Maria Churnosova, Maria Abramova, Denis Plotnikov, Irina Ponomarenko, Evgeny Reshetnikov, Inna Aristova, Inna Sorokina and Mikhail Churnosov

Int. J. Mol. Sci. 2023, 24(9), 7799; https://doi.org/10.3390/ijms24097799 - 25 Apr 2023

Cited by 7 | Viewed by 2002

Abstract

The aim of the study was directed at studying the sex-specific features of the correlation between genome-wide association studies (GWAS)-noticeable polymorphisms and hypertension (HTN). In two groups of European subjects of Russia (n = 1405 in total), such as men (n [...] Read more.

The aim of the study was directed at studying the sex-specific features of the correlation between genome-wide association studies (GWAS)-noticeable polymorphisms and hypertension (HTN). In two groups of European subjects of Russia (n = 1405 in total), such as men (n = 821 in total: n = 564 HTN, n = 257 control) and women (n = 584 in total: n = 375 HTN, n = 209 control), the distribution of ten specially selected polymorphisms (they have confirmed associations of GWAS level with blood pressure (BP) parameters and/or HTN in Europeans) has been considered. The list of studied loci was as follows: (PLCE1) rs932764 A > G, (AC026703.1) rs1173771 G > A, (CERS5) rs7302981 G > A, (HFE) rs1799945 C > G, (OBFC1) rs4387287 C > A, (BAG6) rs805303 G > A, (RGL3) rs167479 T > G, (ARHGAP42) rs633185 C > G, (TBX2) rs8068318 T > C, and (ATP2B1) rs2681472 A > G. The contribution of individual loci and their inter-locus interactions to the HTN susceptibility with bioinformatic interpretation of associative links was evaluated separately in men’s and women’s cohorts. The men–women differences in involvement in the disease of the BP/HTN-associated GWAS SNPs were detected. Among women, the HTN risk has been associated with HFE rs1799945 C > G (genotype GG was risky; OR_GG = 11.15 p_permGG = 0.014) and inter-locus interactions of all 10 examined SNPs as part of 26 intergenic interactions models. In men, the polymorphism BAG6 rs805303 G > A (genotype AA was protective; OR_AA = 0.30 p_permAA = 0.0008) and inter-SNPs interactions of eight loci in only seven models have been founded as HTN-correlated. HTN-linked loci and strongly linked SNPs were characterized by pronounced polyvector functionality in both men and women, but at the same time, signaling pathways of HTN-linked genes/SNPs in women and men were similar and were represented mainly by immune mechanisms. As a result, the present study has demonstrated a more pronounced contribution of BP/HTN-associated GWAS SNPs to the HTN susceptibility (due to weightier intergenic interactions) in European women than in men. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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Review

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20 pages, 2064 KiB

Open AccessReview

Model Systems to Study the Mechanism of Vascular Aging

by Janette van der Linden, Lianne Trap, Caroline V. Scherer, Anton J. M. Roks, A. H. Jan Danser, Ingrid van der Pluijm and Caroline Cheng

Int. J. Mol. Sci. 2023, 24(20), 15379; https://doi.org/10.3390/ijms242015379 - 19 Oct 2023

Cited by 2 | Viewed by 3361

Abstract

Cardiovascular diseases are the leading cause of death globally. Within cardiovascular aging, arterial aging holds significant importance, as it involves structural and functional alterations in arteries that contribute substantially to the overall decline in cardiovascular health during the aging process. As arteries age, [...] Read more.

Cardiovascular diseases are the leading cause of death globally. Within cardiovascular aging, arterial aging holds significant importance, as it involves structural and functional alterations in arteries that contribute substantially to the overall decline in cardiovascular health during the aging process. As arteries age, their ability to respond to stress and injury diminishes, while their luminal diameter increases. Moreover, they experience intimal and medial thickening, endothelial dysfunction, loss of vascular smooth muscle cells, cellular senescence, extracellular matrix remodeling, and deposition of collagen and calcium. This aging process also leads to overall arterial stiffening and cellular remodeling. The process of genomic instability plays a vital role in accelerating vascular aging. Progeria syndromes, rare genetic disorders causing premature aging, exemplify the impact of genomic instability. Throughout life, our DNA faces constant challenges from environmental radiation, chemicals, and endogenous metabolic products, leading to DNA damage and genome instability as we age. The accumulation of unrepaired damages over time manifests as an aging phenotype. To study vascular aging, various models are available, ranging from in vivo mouse studies to cell culture options, and there are also microfluidic in vitro model systems known as vessels-on-a-chip. Together, these models offer valuable insights into the aging process of blood vessels. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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21 pages, 1186 KiB

Open AccessReview

Dysfunctional and Dysregulated Nitric Oxide Synthases in Cardiovascular Disease: Mechanisms and Therapeutic Potential

by Roman Roy, Joshua Wilcox, Andrew J. Webb and Kevin O’Gallagher

Int. J. Mol. Sci. 2023, 24(20), 15200; https://doi.org/10.3390/ijms242015200 - 15 Oct 2023

Cited by 20 | Viewed by 4235

Abstract

Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, [...] Read more.

Nitric oxide (NO) plays an important and diverse signalling role in the cardiovascular system, contributing to the regulation of vascular tone, endothelial function, myocardial function, haemostasis, and thrombosis, amongst many other roles. NO is synthesised through the nitric oxide synthase (NOS)-dependent L-arginine-NO pathway, as well as the nitrate-nitrite-NO pathway. The three isoforms of NOS, namely neuronal (NOS1), inducible (NOS2), and endothelial (NOS3), have different localisation and functions in the human body, and are consequently thought to have differing pathophysiological roles. Furthermore, as we continue to develop a deepened understanding of the different roles of NOS isoforms in disease, the possibility of therapeutically modulating NOS activity has emerged. Indeed, impaired (or dysfunctional), as well as overactive (or dysregulated) NOS activity are attractive therapeutic targets in cardiovascular disease. This review aims to describe recent advances in elucidating the physiological role of NOS isoforms within the cardiovascular system, as well as mechanisms of dysfunctional and dysregulated NOS in cardiovascular disease. We then discuss the modulation of NO and NOS activity as a target in the development of novel cardiovascular therapeutics. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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13 pages, 756 KiB

Open AccessReview

Angiotensin Regulation of Vascular Homeostasis: Exploring the Role of ROS and RAS Blockers

by Nikolaos Koumallos, Evangelia Sigala, Theodoros Milas, Nikolaos G. Baikoussis, Dimitrios Aragiannis, Skevos Sideris and Konstantinos Tsioufis

Int. J. Mol. Sci. 2023, 24(15), 12111; https://doi.org/10.3390/ijms241512111 - 28 Jul 2023

Cited by 6 | Viewed by 1512

Abstract

Extensive research has been conducted to elucidate and substantiate the crucial role of the Renin-Angiotensin System (RAS) in the pathogenesis of hypertension, cardiovascular disorders, and renal diseases. Furthermore, the role of oxidative stress in maintaining vascular balance has been well established. It has [...] Read more.

Extensive research has been conducted to elucidate and substantiate the crucial role of the Renin-Angiotensin System (RAS) in the pathogenesis of hypertension, cardiovascular disorders, and renal diseases. Furthermore, the role of oxidative stress in maintaining vascular balance has been well established. It has been observed that many of the cellular effects induced by Angiotensin II (Ang II) are facilitated by reactive oxygen species (ROS) produced by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. In this paper, we present a comprehensive overview of the role of ROS in the physiology of human blood vessels, specifically focusing on its interaction with RAS. Moreover, we delve into the mechanisms by which clinical interventions targeting RAS influence redox signaling in the vascular wall. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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22 pages, 1884 KiB

Open AccessReview

Smooth Muscle Heterogeneity and Plasticity in Health and Aortic Aneurysmal Disease

by Yunwen Hu, Zhaohua Cai and Ben He

Int. J. Mol. Sci. 2023, 24(14), 11701; https://doi.org/10.3390/ijms241411701 - 20 Jul 2023

Cited by 5 | Viewed by 3040

Abstract

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in the maintenance of aortic wall integrity. VSMCs have been suggested to have contractile and synthetic phenotypes and undergo phenotypic switching [...] Read more.

Vascular smooth muscle cells (VSMCs) are the predominant cell type in the medial layer of the aorta, which plays a critical role in the maintenance of aortic wall integrity. VSMCs have been suggested to have contractile and synthetic phenotypes and undergo phenotypic switching to contribute to the deteriorating aortic wall structure. Recently, the unprecedented heterogeneity and diversity of VSMCs and their complex relationship to aortic aneurysms (AAs) have been revealed by high-resolution research methods, such as lineage tracing and single-cell RNA sequencing. The aortic wall consists of VSMCs from different embryonic origins that respond unevenly to genetic defects that directly or indirectly regulate VSMC contractile phenotype. This difference predisposes to hereditary AAs in the aortic root and ascending aorta. Several VSMC phenotypes with different functions, for example, secreting VSMCs, proliferative VSMCs, mesenchymal stem cell-like VSMCs, immune-related VSMCs, proinflammatory VSMCs, senescent VSMCs, and stressed VSMCs are identified in non-hereditary AAs. The transformation of VSMCs into different phenotypes is an adaptive response to deleterious stimuli but can also trigger pathological remodeling that exacerbates the pathogenesis and development of AAs. This review is intended to contribute to the understanding of VSMC diversity in health and aneurysmal diseases. Papers that give an update on VSMC phenotype diversity in health and aneurysmal disease are summarized and recent insights on the role of VSMCs in AAs are discussed. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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11 pages, 1052 KiB

Open AccessReview

A Receptor Story: Insulin Resistance Pathophysiology and Physiologic Insulin Resensitization’s Role as a Treatment Modality

by Stanley T. Lewis, Frank Greenway, Tori R. Tucker, Michael Alexander, Levonika K. Jackson, Scott A. Hepford, Brian Loveridge and Jonathan R. T. Lakey

Int. J. Mol. Sci. 2023, 24(13), 10927; https://doi.org/10.3390/ijms241310927 - 30 Jun 2023

Cited by 2 | Viewed by 4809

Abstract

Physiologic insulin secretion consists of an oscillating pattern of secretion followed by distinct trough periods that stimulate ligand and receptor activation. Apart from the large postprandial bolus release of insulin, β cells also secrete small amounts of insulin every 4–8 min independent of [...] Read more.

Physiologic insulin secretion consists of an oscillating pattern of secretion followed by distinct trough periods that stimulate ligand and receptor activation. Apart from the large postprandial bolus release of insulin, β cells also secrete small amounts of insulin every 4–8 min independent of a meal. Insulin resistance is associated with a disruption in the normal cyclical pattern of insulin secretion. In the case of type-2 diabetes, β-cell mass is reduced due to apoptosis and β cells secrete insulin asynchronously. When ligand/receptors are constantly exposed to insulin, a negative feedback loop down regulates insulin receptor availability to insulin, creating a relative hyperinsulinemia. The relative excess of insulin leads to insulin resistance (IR) due to decreased receptor availability. Over time, progressive insulin resistance compromises carbohydrate metabolism, and may progress to type-2 diabetes (T2D). In this review, we discuss insulin resistance pathophysiology and the use of dynamic exogenous insulin administration in a manner consistent with more normal insulin secretion periodicity to reverse insulin resistance. Administration of insulin in such a physiologic manner appears to improve insulin sensitivity, lower HgbA1c, and, in some instances, has been associated with the reversal of end-organ damage that leads to complications of diabetes. This review outlines the rationale for how the physiologic secretion of insulin orchestrates glucose metabolism, and how mimicking this secretion profile may serve to improve glycemic control, reduce cellular inflammation, and potentially improve outcomes in patients with diabetes. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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29 pages, 2071 KiB

Open AccessReview

Portrayal of NLRP3 Inflammasome in Atherosclerosis: Current Knowledge and Therapeutic Targets

by Daniela Maria Tanase, Emilia Valasciuc, Evelina Maria Gosav, Anca Ouatu, Oana Nicoleta Buliga-Finis, Mariana Floria, Minela Aida Maranduca and Ionela Lacramioara Serban

Int. J. Mol. Sci. 2023, 24(9), 8162; https://doi.org/10.3390/ijms24098162 - 3 May 2023

Cited by 17 | Viewed by 3127

Abstract

We are witnessing the globalization of a specific type of arteriosclerosis with rising prevalence, incidence and an overall cardiovascular disease burden. Currently, atherosclerosis increasingly affects the younger generation as compared to previous decades. While early preventive medicine has seen improvements, research advances in [...] Read more.

We are witnessing the globalization of a specific type of arteriosclerosis with rising prevalence, incidence and an overall cardiovascular disease burden. Currently, atherosclerosis increasingly affects the younger generation as compared to previous decades. While early preventive medicine has seen improvements, research advances in laboratory and clinical investigation promise to provide us with novel diagnosis tools. Given the physio-pathological complexity and epigenetic patterns of atherosclerosis and the discovery of new molecules involved, the therapeutic field of atherosclerosis has room for substantial growth. Thus, the scientific community is currently investigating the role of nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, a crucial component of the innate immune system in different inflammatory disorders. NLRP3 is activated by distinct factors and numerous cellular and molecular events which trigger NLRP3 inflammasome assembly with subsequent cleavage of pro-interleukin (IL)-1β and pro-IL-18 pathways via caspase-1 activation, eliciting endothelial dysfunction, promotion of oxidative stress and the inflammation process of atherosclerosis. In this review, we introduce the basic cellular and molecular mechanisms of NLRP3 inflammasome activation and its role in atherosclerosis. We also emphasize its promising therapeutic pharmaceutical potential. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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24 pages, 1152 KiB

Open AccessReview

The Role of Oxidative Stress Enhanced by Adiposity in Cardiometabolic Diseases

by Iwona Świątkiewicz, Marcin Wróblewski, Jarosław Nuszkiewicz, Paweł Sutkowy, Joanna Wróblewska and Alina Woźniak

Int. J. Mol. Sci. 2023, 24(7), 6382; https://doi.org/10.3390/ijms24076382 - 28 Mar 2023

Cited by 24 | Viewed by 3826

Abstract

Cardiometabolic diseases (CMDs), including cardiovascular disease (CVD), metabolic syndrome (MetS), and type 2 diabetes (T2D), are associated with increased morbidity and mortality. The growing prevalence of CVD is mostly attributed to the aging population and common occurrence of risk factors, such as high [...] Read more.

Cardiometabolic diseases (CMDs), including cardiovascular disease (CVD), metabolic syndrome (MetS), and type 2 diabetes (T2D), are associated with increased morbidity and mortality. The growing prevalence of CVD is mostly attributed to the aging population and common occurrence of risk factors, such as high systolic blood pressure, elevated plasma glucose, and increased body mass index, which led to a global epidemic of obesity, MetS, and T2D. Oxidant–antioxidant balance disorders largely contribute to the pathogenesis and outcomes of CMDs, such as systemic essential hypertension, coronary artery disease, stroke, and MetS. Enhanced and disturbed generation of reactive oxygen species in excess adipose tissue during obesity may lead to increased oxidative stress. Understanding the interplay between adiposity, oxidative stress, and cardiometabolic risks can have translational impacts, leading to the identification of novel effective strategies for reducing the CMDs burden. The present review article is based on extant results from basic and clinical studies and specifically addresses the various aspects associated with oxidant–antioxidant balance disorders in the course of CMDs in subjects with excess adipose tissue accumulation. We aim at giving a comprehensive overview of existing knowledge, knowledge gaps, and future perspectives for further basic and clinical research. We provide insights into both the mechanisms and clinical implications of effects related to the interplay between adiposity and oxidative stress for treating and preventing CMDs. Future basic research and clinical trials are needed to further examine the mechanisms of adiposity-enhanced oxidative stress in CMDs and the efficacy of antioxidant therapies for reducing risk and improving outcome of patients with CMDs. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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24 pages, 843 KiB

Open AccessReview

The Role of the Gut Microbiome and Trimethylamine Oxide in Atherosclerosis and Age-Related Disease

by Racha El Hage, Nada Al-Arawe and Irene Hinterseher

Int. J. Mol. Sci. 2023, 24(3), 2399; https://doi.org/10.3390/ijms24032399 - 25 Jan 2023

Cited by 15 | Viewed by 6578

Abstract

The gut microbiome plays a major role in human health, and gut microbial imbalance or dysbiosis is associated with disease development. Modulation in the gut microbiome can be used to treat or prevent different diseases. Gut dysbiosis increases with aging, and it has [...] Read more.

The gut microbiome plays a major role in human health, and gut microbial imbalance or dysbiosis is associated with disease development. Modulation in the gut microbiome can be used to treat or prevent different diseases. Gut dysbiosis increases with aging, and it has been associated with the impairment of gut barrier function leading to the leakage of harmful metabolites such as trimethylamine (TMA). TMA is a gut metabolite resulting from dietary amines that originate from animal-based foods. TMA enters the portal circulation and is oxidized by the hepatic enzyme into trimethylamine oxide (TMAO). Increased TMAO levels have been reported in elderly people. High TMAO levels are linked to peripheral artery disease (PAD), endothelial senescence, and vascular aging. Emerging evidence showed the beneficial role of probiotics and prebiotics in the management of several atherogenic risk factors through the remodeling of the gut microbiota, thus leading to a reduction in TMAO levels and atherosclerotic lesions. Despite the promising outcomes in different studies, the definite mechanisms of gut dysbiosis and microbiota-derived TMAO involved in atherosclerosis remain not fully understood. More studies are still required to focus on the molecular mechanisms and precise treatments targeting gut microbiota and leading to atheroprotective effects. Full article

(This article belongs to the Special Issue New Trends in Diabetes, Hypertension and Cardiovascular Diseases)

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