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Open AccessEditorial

Editorial of the Special Issue: Cellular Mechanisms of Cardiovascular Disease

by Tânia Martins-Marques, Gonçalo Coutinho and Attila Kiss

Biomedicines 2023, 11(9), 2494; https://doi.org/10.3390/biomedicines11092494 - 8 Sep 2023

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Abstract

Cardiovascular diseases (CVD) remain the major cause of mortality and disability worldwide, having contributed to 19 [...] Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

Research

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16 pages, 2178 KiB

Open AccessArticle

H₂S Prodrug, SG-1002, Protects against Myocardial Oxidative Damage and Hypertrophy In Vitro via Induction of Cystathionine β-Synthase and Antioxidant Proteins

by Rahib K. Islam, Erinn Donnelly, Erminia Donnarumma, Fokhrul Hossain, Jason D. Gardner and Kazi N. Islam

Biomedicines 2023, 11(2), 612; https://doi.org/10.3390/biomedicines11020612 - 18 Feb 2023

Cited by 8 | Viewed by 2421

Abstract

Endogenously produced hydrogen sulfide (H₂S) is critical for cardiovascular homeostasis. Therapeutic strategies aimed at increasing H₂S levels have proven cardioprotective in models of acute myocardial infarction (MI) and heart failure (HF). The present study was undertaken to investigate the [...] Read more.

Endogenously produced hydrogen sulfide (H₂S) is critical for cardiovascular homeostasis. Therapeutic strategies aimed at increasing H₂S levels have proven cardioprotective in models of acute myocardial infarction (MI) and heart failure (HF). The present study was undertaken to investigate the effects of a novel H₂S prodrug, SG-1002, on stress induced hypertrophic signaling in murine HL-1 cardiac muscle cells. Treatment of HL-1 cells with SG-1002 under serum starvation without or with H₂O₂ increased the levels of H₂S, H₂S producing enzyme, and cystathionine β-synthase (CBS), as well as antioxidant protein levels, such as super oxide dismutase1 (SOD1) and catalase, and additionally decreased oxidative stress. SG-1002 also decreased the expression of hypertrophic/HF protein markers such as atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), galectin-3, TIMP1, collagen type III, and TGF-β1 in stressed HL-1 cells. Treatment with SG-1002 caused a significant induction of cell viability and a marked reduction of cellular cytotoxicity in HL-1 cells under serum starvation incubated without or with H₂O₂. Experimental results of this study suggest that SG-1002 attenuates myocardial cellular oxidative damage and/or hypertrophic signaling via increasing H₂S levels or H₂S producing enzymes, CBS, and antioxidant proteins. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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11 pages, 2158 KiB

Open AccessArticle

Purinergic Signaling in Pathologic Osteogenic Differentiation of Aortic Valve Interstitial Cells from Patients with Aortic Valve Calcification

by Polina Klauzen, Daria Semenova, Daria Kostina, Vladimir Uspenskiy and Anna Malashicheva

Biomedicines 2023, 11(2), 307; https://doi.org/10.3390/biomedicines11020307 - 21 Jan 2023

Cited by 3 | Viewed by 1712

Abstract

Purinergic signaling is associated with a vast spectrum of physiological processes, including cardiovascular system function and, in particular, its pathological calcifications, such as aortic valve stenosis. Aortic valve stenosis (AS) is a degenerative disease for which there is no cure other than surgical [...] Read more.

Purinergic signaling is associated with a vast spectrum of physiological processes, including cardiovascular system function and, in particular, its pathological calcifications, such as aortic valve stenosis. Aortic valve stenosis (AS) is a degenerative disease for which there is no cure other than surgical replacement of the affected valve. Purinergic signaling is known to be involved in the pathologic osteogenic differentiation of valve interstitial cells (VIC) into osteoblast-like cells, which underlies the pathogenesis of AS. ATP, its metabolites and related nucleotides also act as signaling molecules in normal osteogenic differentiation, which is observed in pro-osteoblasts and leads to bone tissue development. We show that stenotic and non-stenotic valve interstitial cells significantly differ from each other, especially under osteogenic stimuli. In osteogenic conditions, the expression of the ecto-nucleotidases ENTPD1 and ENPP1, as well as ADORA2b, is increased in AS VICs compared to normal VICs. In addition, AS VICs after osteogenic stimulation look more similar to osteoblasts than non-stenotic VICs in terms of purinergic signaling, which suggests the stronger osteogenic differentiation potential of AS VICs. Thus, purinergic signaling is impaired in stenotic aortic valves and might be used as a potential target in the search for an anti-calcification therapy. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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14 pages, 2231 KiB

Open AccessArticle

Kawasaki Disease-like Vasculitis Facilitates Atherosclerosis, and Statin Shows a Significant Antiatherosclerosis and Anti-Inflammatory Effect in a Kawasaki Disease Model Mouse

by Yusuke Motoji, Ryuji Fukazawa, Ryosuke Matsui, Noriko Nagi-Miura, Yasuo Miyagi, Yasuhiko Itoh and Yosuke Ishii

Biomedicines 2022, 10(8), 1794; https://doi.org/10.3390/biomedicines10081794 - 26 Jul 2022

Cited by 7 | Viewed by 2326

Abstract

Kawasaki disease (KD) is an acute form of systemic vasculitis that may promote atherosclerosis in adulthood. This study examined the relationships between KD, atherosclerosis, and the long-term effects of HMG-CoA inhibitors (statins). Candida albicans water-soluble fraction (CAWS) was injected intraperitoneally into 5-week-old male [...] Read more.

Kawasaki disease (KD) is an acute form of systemic vasculitis that may promote atherosclerosis in adulthood. This study examined the relationships between KD, atherosclerosis, and the long-term effects of HMG-CoA inhibitors (statins). Candida albicans water-soluble fraction (CAWS) was injected intraperitoneally into 5-week-old male apolipoprotein-E-deficient (Apo E-/-) mice to create KD-like vasculitis. Mice were divided into 4 groups: the control, CAWS, CAWS+statin, and late-statin groups. They were sacrificed at 6 or 10 weeks after injection. Statin was started after CAWS injection in all groups except the late-statin group, which was administered statin internally 6 weeks after injection. Lipid plaque lesions on the aorta were evaluated with Oil Red O. The aortic root and abdominal aorta were evaluated with hematoxylin and eosin staining and immunostaining. CAWS vasculitis significantly enhanced aortic atherosclerosis and inflammatory cell invasion into the aortic root and abdominal aorta. Statins significantly inhibited atherosclerosis and inflammatory cell invasion, including macrophages. CAWS vasculitis, a KD-like vasculitis, promoted atherosclerosis in Apo E-/- mice. The long-term oral administration of statin significantly suppressed not only atherosclerosis but also inflammatory cell infiltration. Therefore, statin treatment may be used for the secondary prevention of cardiovascular events during the chronic phase of KD. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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17 pages, 3548 KiB

Open AccessArticle

Saxagliptin Cardiotoxicity in Chronic Heart Failure: The Role of DPP4 in the Regulation of Neuropeptide Tone

by Imre Vörös, Zsófia Onódi, Viktória Éva Tóth, Tamás G. Gergely, Éva Sághy, Anikó Görbe, Ágnes Kemény, Przemyslaw Leszek, Zsuzsanna Helyes, Péter Ferdinandy and Zoltán V. Varga

Biomedicines 2022, 10(7), 1573; https://doi.org/10.3390/biomedicines10071573 - 1 Jul 2022

Cited by 7 | Viewed by 3395

Abstract

Dipeptidyl-peptidase-4 (DPP4) inhibitors are novel medicines for diabetes. The SAVOR-TIMI-53 clinical trial revealed increased heart-failure-associated hospitalization in saxagliptin-treated patients. Although this side effect could limit therapeutic use, the mechanism of this potential cardiotoxicity is unclear. We aimed to establish a cellular platform to [...] Read more.

Dipeptidyl-peptidase-4 (DPP4) inhibitors are novel medicines for diabetes. The SAVOR-TIMI-53 clinical trial revealed increased heart-failure-associated hospitalization in saxagliptin-treated patients. Although this side effect could limit therapeutic use, the mechanism of this potential cardiotoxicity is unclear. We aimed to establish a cellular platform to investigate DPP4 inhibition and the role of its neuropeptide substrates substance P (SP) and neuropeptide Y (NPY), and to determine the expression of DDP4 and its neuropeptide substrates in the human heart. Western blot, radio-, enzyme-linked immuno-, and RNA scope assays were performed to investigate the expression of DPP4 and its substrates in human hearts. Calcein-based viability measurements and scratch assays were used to test the potential toxicity of DPP4 inhibitors. Cardiac expression of DPP4 and NPY decreased in heart failure patients. In human hearts, DPP4 mRNA is detectable mainly in cardiomyocytes and endothelium. Treatment with DPP4 inhibitors alone/in combination with neuropeptides did not affect viability but in scratch assays neuropeptides decreased, while saxagliptin co-administration increased fibroblast migration in isolated neonatal rat cardiomyocyte-fibroblast co-culture. Decreased DPP4 activity takes part in the pathophysiology of end-stage heart failure. DPP4 compensates against the elevated sympathetic activity and altered neuropeptide tone. Its inhibition decreases this adaptive mechanism, thereby exacerbating myocardial damage. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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17 pages, 3808 KiB

Open AccessArticle

Mechanisms of Regenerative Potential Activation in Cardiac Mesenchymal Cells

by Pavel M. Docshin, Andrei A. Karpov, Malik V. Mametov, Dmitry Y. Ivkin, Anna A. Kostareva and Anna B. Malashicheva

Biomedicines 2022, 10(6), 1283; https://doi.org/10.3390/biomedicines10061283 - 31 May 2022

Cited by 7 | Viewed by 2648

Abstract

Recovery of the contractile function of the heart and the regeneration of the myocardium after ischemic injury are contemporary issues in regenerative medicine and cell biology. This study aimed to analyze early transcriptional events in cardiac tissue after infarction and to explore the [...] Read more.

Recovery of the contractile function of the heart and the regeneration of the myocardium after ischemic injury are contemporary issues in regenerative medicine and cell biology. This study aimed to analyze early transcriptional events in cardiac tissue after infarction and to explore the cell population that can be isolated from myocardial tissue. We induced myocardial infarction in Wistar rats by permanent ligation of the left coronary artery and showed a change in the expression pattern of Notch-associated genes and Bmp2/Runx2 in post-MI tissues using RNA sequencing and RT-PCR. We obtained primary cardiac mesenchymal cell (CMC) cultures from postinfarction myocardium by enzymatic dissociation of tissues, which retained part of the activation stimulus and had a pronounced proliferative potential, assessed using a “xCELLigence” real-time system. Hypoxia in vitro also causes healthy CMCs to overexpress Notch-associated genes and Bmp2/Runx2. Exogenous activation of the Notch signaling pathway by lentiviral transduction of healthy CMCs resulted in a dose-dependent activation of the Runx2 transcription factor but did not affect the activity of the Bmp2 factor. Thus, the results of this study showed that acute hypoxic stress could cause short-term activation of the embryonic signaling pathways Notch and Bmp in CMCs, and this interaction is closely related to the processes of early myocardial remodeling after a heart attack. The ability to correctly modulate and control the corresponding signals in the heart can help increase the regenerative capacity of the myocardium before the formation of fibrotic conditions. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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16 pages, 3784 KiB

Open AccessEditor’s ChoiceArticle

Gasdermin D Deficiency Limits the Transition of Atherosclerotic Plaques to an Inflammatory Phenotype in ApoE Knock-Out Mice

by Pauline Puylaert, Melissa Van Praet, Frederik Vaes, Cédric H. G. Neutel, Lynn Roth, Pieter-Jan Guns, Guido R. Y. De Meyer and Wim Martinet

Biomedicines 2022, 10(5), 1171; https://doi.org/10.3390/biomedicines10051171 - 19 May 2022

Cited by 25 | Viewed by 3790

Abstract

Gasdermin D (GSDMD) is the key executor of pyroptotic cell death. Recent studies suggest that GSDMD-mediated pyroptosis is involved in atherosclerotic plaque destabilization. We report that cleaved GSDMD is expressed in macrophage- and smooth muscle cell-rich areas of human plaques. To determine the [...] Read more.

Gasdermin D (GSDMD) is the key executor of pyroptotic cell death. Recent studies suggest that GSDMD-mediated pyroptosis is involved in atherosclerotic plaque destabilization. We report that cleaved GSDMD is expressed in macrophage- and smooth muscle cell-rich areas of human plaques. To determine the effects of GSDMD deficiency on atherogenesis, ApoE^−/− Gsdmd^−/− (n = 16) and ApoE^−/−Gsdmd^+/+ (n = 18) mice were fed a western-type diet for 16 weeks. Plaque initiation and formation of stable proximal aortic plaques were not altered. However, plaques in the brachiocephalic artery (representing more advanced lesions compared to aortic plaques) of ApoE^−/− Gsdmd^−/− mice were significantly smaller (115 ± 18 vs. 186 ± 16 × 10³ µm², p = 0.006) and showed features of increased stability, such as decreased necrotic core area (19 ± 4 vs. 37 ± 7 × 10³ µm², p = 0.03) and increased αSMA/MAC3 ratio (1.6 ± 0.3 vs. 0.7 ± 0.1, p = 0.01), which was also observed in proximal aortic plaques. Interestingly, a significant increase in TUNEL positive cells was observed in brachiocephalic artery plaques from ApoE^−/− Gsdmd^−/− mice (141 ± 25 vs. 62 ± 8 cells/mm², p = 0.005), indicating a switch to apoptosis. This switch from pyroptosis to apoptosis was also observed in vitro in Gsdmd^−/− macrophages. In conclusion, targeting GSDMD appears to be a promising approach for limiting the transition to an inflammatory, vulnerable plaque phenotype. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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13 pages, 1356 KiB

Open AccessArticle

DNMT3B System Dysregulation Contributes to the Hypomethylated State in Ischaemic Human Hearts

by Estefanía Tarazón, Lorena Pérez-Carrillo, Isaac Giménez-Escamilla, María García-Manzanares, Luis Martínez-Dolz, Manuel Portolés and Esther Roselló-Lletí

Biomedicines 2022, 10(4), 866; https://doi.org/10.3390/biomedicines10040866 - 7 Apr 2022

Cited by 3 | Viewed by 2212

Abstract

A controversial understanding of the state of the DNA methylation machinery exists in ischaemic cardiomyopathy (ICM). Moreover, its relationship to other epigenetic alterations is incomplete. Therefore, we carried out an in-depth study of the DNA methylation process in human cardiac tissue. We showed [...] Read more.

A controversial understanding of the state of the DNA methylation machinery exists in ischaemic cardiomyopathy (ICM). Moreover, its relationship to other epigenetic alterations is incomplete. Therefore, we carried out an in-depth study of the DNA methylation process in human cardiac tissue. We showed a dysregulation of the DNA methylation machinery accordingly with the genome-wide hypomethylation that we observed: specifically, an overexpression of main genes involved in the elimination of methyl groups (TET1, SMUG1), and underexpression of molecules implicated in the maintenance of methylation (MBD2, UHRF1). By contrast, we found DNMT3B upregulation, a key molecule in the addition of methyl residues in DNA, and an underexpression of miR-133a-3p, an inhibitor of DNMT3B transcription. However, we found many relevant alterations that would counteract the upregulation observed, such as the overexpression of TRAF6, responsible for Dnmt3b degradation. Furthermore, we showed that molecules regulating Dnmts activity were altered; specifically, SAM/SAH ratio reduction. All these results are in concordance with the Dnmts normal function that we show. Our analysis revealed genome-wide hypomethylation along with dysregulation in the mechanisms of addition, elimination and maintenance of methyl groups in the DNA of ICM. We describe relevant alterations in the DNMT3B system, which promote a normal Dnmt3b function despite its upregulation. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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17 pages, 4183 KiB

Open AccessArticle

Association of Plasma Methylglyoxal Increase after Myocardial Infarction and the Left Ventricular Ejection Fraction

by Stefan Heber, Paul M. Haller, Attila Kiss, Bernhard Jäger, Kurt Huber and Michael J. M. Fischer

Biomedicines 2022, 10(3), 605; https://doi.org/10.3390/biomedicines10030605 - 4 Mar 2022

Cited by 4 | Viewed by 2181

Abstract

Background: Preclinical studies suggest that methylglyoxal (MG) increases within the myocardium upon acute myocardial infarction (AMI) and thereafter contributes to adverse postinfarct remodeling. The aims of this study were to test whether MG increases in plasma of humans after AMI and whether this [...] Read more.

Background: Preclinical studies suggest that methylglyoxal (MG) increases within the myocardium upon acute myocardial infarction (AMI) and thereafter contributes to adverse postinfarct remodeling. The aims of this study were to test whether MG increases in plasma of humans after AMI and whether this increase is related to the left ventricular ejection fraction (LVEF). Methods: The plasma samples of 37 patients with ST elevation AMI undergoing primary percutaneous coronary intervention (pPCI) acquired in a previously conducted randomized controlled trial testing remote ischemic conditioning (RIC) were analyzed by means of high-performance liquid chromatography. Time courses of the variables were analyzed by means of mixed linear models. Multiple regression analyses served to explore the relationship between MG levels and the LVEF. Results: Compared to the MG levels upon admission due to AMI, the levels were increased 2.4-fold (95% CI, 1.6–3.6) 0.5 h after reperfusion facilitated by pPCI, 2.6-fold (1.7–4.0) after 24 h and largely returned to the baseline after 30 d (1.1-fold, 0.8–1.5). The magnitude of the MG increase was largely independent of that of cardiac necrosis markers. Overall, the highest MG values within 24 h after AMI were associated with the lowest LVEF after 4 d. While markers of myocardial necrosis and stretch quantified within the first 24 h explained 52% of the variance of the LVEF, MG explained additional 23% of the variance (p < 0.001). Conclusions: Considering these observational data, it is plausible that the preclinical finding of MG generation after AMI negatively affecting the LVEF also applies to humans. Inhibition of MG generation or MG scavenging might provide a novel therapeutic strategy to target post-AMI myocardial remodeling and dysfunction. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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Review

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20 pages, 655 KiB

Open AccessReview

Cardiotoxicity of Selected Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Renal Cell Carcinoma

by Beata Franczyk, Jacek Rysz, Janusz Ławiński, Aleksandra Ciałkowska-Rysz and Anna Gluba-Brzózka

Biomedicines 2023, 11(1), 181; https://doi.org/10.3390/biomedicines11010181 - 11 Jan 2023

Cited by 6 | Viewed by 2844

Abstract

Renal cell carcinoma (RCC) is one of the most frequent malignant neoplasms of the kidney. The therapeutic options available for the treatment of advanced or metastatic RCC include vascular endothelial growth factor receptor (VEGFR)-targeted molecules, for example, tyrosine kinase inhibitors (TKI). Various VEGFR-TKIs [...] Read more.

Renal cell carcinoma (RCC) is one of the most frequent malignant neoplasms of the kidney. The therapeutic options available for the treatment of advanced or metastatic RCC include vascular endothelial growth factor receptor (VEGFR)-targeted molecules, for example, tyrosine kinase inhibitors (TKI). Various VEGFR-TKIs proved to be effective in the treatment of patients with solid tumours. The combination of two drugs may prove most beneficial in the treatment of metastatic RCC; however, it also enhances the risk of toxicity compared to monotherapy. Specific VEGFR-TKIs (e.g., sunitinib, sorafenib or pazopanib) may increase the rate of cardiotoxicity in metastatic settings. VEGF inhibitors modulate multiple signalling pathways; thus, the identification of the mechanism underlying cardiotoxicity appears challenging. VEGF signalling is vital for the maintenance of cardiomyocyte homeostasis and cardiac function; therefore, its inhibition can be responsible for the reported adverse effects. Disturbed growth factor signalling pathways may be associated with endothelial dysfunction, impaired revascularization, the development of dilated cardiomyopathy, cardiac hypertrophies and altered peripheral vascular load. Patients at high cardiovascular risk at baseline could benefit from clinical follow-up in the first 2–4 weeks after the introduction of targeted molecular therapy; however, there is no consensus concerning the surveillance strategy. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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16 pages, 1419 KiB

Open AccessReview

Cellular Mechanisms of Coronary Artery Spasm

by Beata Franczyk, Jill Dybiec, Weronika Frąk, Julia Krzemińska, Joanna Kućmierz, Ewelina Młynarska, Magdalena Szlagor, Magdalena Wronka and Jacek Rysz

Biomedicines 2022, 10(10), 2349; https://doi.org/10.3390/biomedicines10102349 - 21 Sep 2022

Cited by 10 | Viewed by 4996

Abstract

Coronary artery spasm (CAS) is a reversible phenomenon caused by spontaneous excessive vascular smooth muscle contractility and vascular wall hypertonicity, which results in partial or complete closure of the lumen of normal or atherosclerotic coronary arteries. The clinical picture of CAS includes chest [...] Read more.

Coronary artery spasm (CAS) is a reversible phenomenon caused by spontaneous excessive vascular smooth muscle contractility and vascular wall hypertonicity, which results in partial or complete closure of the lumen of normal or atherosclerotic coronary arteries. The clinical picture of CAS includes chest discomfort which is similar in quality to that of stable effort angina. Mechanisms underlying the development of CAS are still unclear. CAS certainly is a multifactorial disease. In this review, we paid attention to the role of the main pathophysiologic mechanisms in CAS: endothelial dysfunction, chronic inflammation, oxidative stress, smooth muscle hypercontractility, atherosclerosis and thrombosis, and mutations leading to deficient aldehyde dehydrogenase 2 (ALDH2) activity. These findings might shed novel insight on the underlying mechanisms and identify potential diagnostic and therapeutic targets for cardiovascular diseases in the future. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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16 pages, 650 KiB

Open AccessReview

Suppression of Cardiogenic Edema with Sodium–Glucose Cotransporter-2 Inhibitors in Heart Failure with Reduced Ejection Fraction: Mechanisms and Insights from Pre-Clinical Studies

by Ryan D. Sullivan, Mariana E. McCune, Michelle Hernandez, Guy L. Reed and Inna P. Gladysheva

Biomedicines 2022, 10(8), 2016; https://doi.org/10.3390/biomedicines10082016 - 19 Aug 2022

Cited by 6 | Viewed by 3210

Abstract

In heart failure with reduced ejection fraction (HFrEF), cardiogenic edema develops from impaired cardiac function, pathological remodeling, chronic inflammation, endothelial dysfunction, neurohormonal activation, and altered nitric oxide-related pathways. Pre-clinical HFrEF studies have shown that treatment with sodium–glucose cotransporter-2 inhibitors (SGLT-2i) stimulates natriuretic and [...] Read more.

In heart failure with reduced ejection fraction (HFrEF), cardiogenic edema develops from impaired cardiac function, pathological remodeling, chronic inflammation, endothelial dysfunction, neurohormonal activation, and altered nitric oxide-related pathways. Pre-clinical HFrEF studies have shown that treatment with sodium–glucose cotransporter-2 inhibitors (SGLT-2i) stimulates natriuretic and osmotic/diuretic effects, improves overall cardiac function, attenuates maladaptive cardiac remodeling, and reduces chronic inflammation, oxidative stress, and endothelial dysfunction. Here, we review the mechanisms and effects of SGLT-2i therapy on cardiogenic edema in various models of HFrEF. Overall, the data presented suggest a high translational importance of these studies, and pre-clinical studies show that SGLT-2i therapy has a marked effect on suppressing the progression of HFrEF through multiple mechanisms, including those that affect the development of cardiogenic edema. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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17 pages, 1200 KiB

Open AccessReview

Pathophysiology of Cardiovascular Diseases: New Insights into Molecular Mechanisms of Atherosclerosis, Arterial Hypertension, and Coronary Artery Disease

by Weronika Frąk, Armanda Wojtasińska, Wiktoria Lisińska, Ewelina Młynarska, Beata Franczyk and Jacek Rysz

Biomedicines 2022, 10(8), 1938; https://doi.org/10.3390/biomedicines10081938 - 10 Aug 2022

Cited by 91 | Viewed by 20928

Abstract

Cardiovascular diseases (CVDs) are disorders associated with the heart and circulatory system. Atherosclerosis is its major underlying cause. CVDs are chronic and can remain hidden for a long time. Moreover, CVDs are the leading cause of global morbidity and mortality, thus creating a [...] Read more.

Cardiovascular diseases (CVDs) are disorders associated with the heart and circulatory system. Atherosclerosis is its major underlying cause. CVDs are chronic and can remain hidden for a long time. Moreover, CVDs are the leading cause of global morbidity and mortality, thus creating a major public health concern. This review summarizes the available information on the pathophysiological implications of CVDs, focusing on coronary artery disease along with atherosclerosis as its major cause and arterial hypertension. We discuss the endothelium dysfunction, inflammatory factors, and oxidation associated with atherosclerosis. Mechanisms such as dysfunction of the endothelium and inflammation, which have been identified as critical pathways for development of coronary artery disease, have become easier to diagnose in recent years. Relatively recently, evidence has been found indicating that interactions of the molecular and cellular elements such as matrix metalloproteinases, elements of the immune system, and oxidative stress are involved in the pathophysiology of arterial hypertension. Many studies have revealed several important inflammatory and genetic risk factors associated with CVDs. However, further investigation is crucial to improve our knowledge of CVDs progression and, more importantly, accelerate basic research to improve our understanding of the mechanism of pathophysiology. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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14 pages, 1036 KiB

Open AccessReview

Cardiac Acetylation in Metabolic Diseases

by Emilie Dubois-Deruy, Yara El Masri, Annie Turkieh, Philippe Amouyel, Florence Pinet and Jean-Sébastien Annicotte

Biomedicines 2022, 10(8), 1834; https://doi.org/10.3390/biomedicines10081834 - 29 Jul 2022

Cited by 8 | Viewed by 3894

Abstract

Lysine acetylation is a highly conserved mechanism that affects several biological processes such as cell growth, metabolism, enzymatic activity, subcellular localization of proteins, gene transcription or chromatin structure. This post-translational modification, mainly regulated by lysine acetyltransferase (KAT) and lysine deacetylase (KDAC) enzymes, can [...] Read more.

Lysine acetylation is a highly conserved mechanism that affects several biological processes such as cell growth, metabolism, enzymatic activity, subcellular localization of proteins, gene transcription or chromatin structure. This post-translational modification, mainly regulated by lysine acetyltransferase (KAT) and lysine deacetylase (KDAC) enzymes, can occur on histone or non-histone proteins. Several studies have demonstrated that dysregulated acetylation is involved in cardiac dysfunction, associated with metabolic disorder or heart failure. Since the prevalence of obesity, type 2 diabetes or heart failure rises and represents a major cause of cardiovascular morbidity and mortality worldwide, cardiac acetylation may constitute a crucial pathway that could contribute to disease development. In this review, we summarize the mechanisms involved in the regulation of cardiac acetylation and its roles in physiological conditions. In addition, we highlight the effects of cardiac acetylation in physiopathology, with a focus on obesity, type 2 diabetes and heart failure. This review sheds light on the major role of acetylation in cardiovascular diseases and emphasizes KATs and KDACs as potential therapeutic targets for heart failure. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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27 pages, 1473 KiB

Open AccessReview

Mitochondrial Determinants of Anti-Cancer Drug-Induced Cardiotoxicity

by Carmine Rocca, Ernestina Marianna De Francesco, Teresa Pasqua, Maria Concetta Granieri, Anna De Bartolo, Maria Eugenia Gallo Cantafio, Maria Grazia Muoio, Massimo Gentile, Antonino Neri, Tommaso Angelone, Giuseppe Viglietto and Nicola Amodio

Biomedicines 2022, 10(3), 520; https://doi.org/10.3390/biomedicines10030520 - 22 Feb 2022

Cited by 18 | Viewed by 4920

Abstract

Mitochondria are key organelles for the maintenance of myocardial tissue homeostasis, playing a pivotal role in adenosine triphosphate (ATP) production, calcium signaling, redox homeostasis, and thermogenesis, as well as in the regulation of crucial pathways involved in cell survival. On this basis, it [...] Read more.

Mitochondria are key organelles for the maintenance of myocardial tissue homeostasis, playing a pivotal role in adenosine triphosphate (ATP) production, calcium signaling, redox homeostasis, and thermogenesis, as well as in the regulation of crucial pathways involved in cell survival. On this basis, it is not surprising that structural and functional impairments of mitochondria can lead to contractile dysfunction, and have been widely implicated in the onset of diverse cardiovascular diseases, including ischemic cardiomyopathy, heart failure, and stroke. Several studies support mitochondrial targets as major determinants of the cardiotoxic effects triggered by an increasing number of chemotherapeutic agents used for both solid and hematological tumors. Mitochondrial toxicity induced by such anticancer therapeutics is due to different mechanisms, generally altering the mitochondrial respiratory chain, energy production, and mitochondrial dynamics, or inducing mitochondrial oxidative/nitrative stress, eventually culminating in cell death. The present review summarizes key mitochondrial processes mediating the cardiotoxic effects of anti-neoplastic drugs, with a specific focus on anthracyclines (ANTs), receptor tyrosine kinase inhibitors (RTKIs) and proteasome inhibitors (PIs). Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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Other

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30 pages, 1765 KiB

Open AccessSystematic Review

Worsening Thrombotic Complication of Atherosclerotic Plaques Due to Neutrophils Extracellular Traps: A Systematic Review

by Francesco Nappi, Francesca Bellomo and Sanjeet Singh Avtaar Singh

Biomedicines 2023, 11(1), 113; https://doi.org/10.3390/biomedicines11010113 - 2 Jan 2023

Cited by 11 | Viewed by 2799

Abstract

Neutrophil extracellular traps (NETs) recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA, extruded by activated or dying neutrophils, decorated with various protein mediators, become solid-state reactors that can localize at the critical interface of blood [...] Read more.

Neutrophil extracellular traps (NETs) recently emerged as a newly recognized contributor to venous and arterial thrombosis. These strands of DNA, extruded by activated or dying neutrophils, decorated with various protein mediators, become solid-state reactors that can localize at the critical interface of blood with the intimal surface of diseased arteries alongside propagating and amplifying the regional injury. NETs thus furnish a previously unsuspected link between inflammation, innate immunity, thrombosis, oxidative stress, and cardiovascular diseases. In response to disease-relevant stimuli, neutrophils undergo a specialized series of reactions that culminate in NET formation. DNA derived from either nuclei or mitochondria can contribute to NET formation. The DNA liberated from neutrophils forms a reticular mesh that resembles morphologically a net, rendering the acronym NETs particularly appropriate. The DNA backbone of NETs not only presents intrinsic neutrophil proteins (e.g., MPO (myeloperoxidase) and various proteinases) but can congregate other proteins found in blood (e.g., tissue factor procoagulant). This systematic review discusses the current hypothesis of neutrophil biology, focusing on the triggers and mechanisms of NET formation. Furthermore, the contribution of NETs to atherosclerosis and thrombosis is extensively addressed. Again, the use of NET markers in clinical trials was considered. Ultimately, given the vast body of the published literature, we aim to integrate the experimental evidence with the growing body of clinical information relating to NET critically. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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13 pages, 1397 KiB

Open AccessBrief Report

The Effect of Nutritional Ketosis on Aquaporin Expression in Apolipoprotein E-Deficient Mice: Potential Implications for Energy Homeostasis

by Inês V. da Silva, Sean Gullette, Cristina Florindo, Neil K. Huang, Thomas Neuberger, A. Catharine Ross, Graça Soveral and Rita Castro

Biomedicines 2022, 10(5), 1159; https://doi.org/10.3390/biomedicines10051159 - 18 May 2022

Cited by 6 | Viewed by 2541

Abstract

Ketogenic diets (KDs) are very low-carbohydrate, very high-fat diets which promote nutritional ketosis and impact energetic metabolism. Aquaporins (AQPs) are transmembrane channels that facilitate water and glycerol transport across cell membranes and are critical players in energy homeostasis. Altered AQP expression or function [...] Read more.

Ketogenic diets (KDs) are very low-carbohydrate, very high-fat diets which promote nutritional ketosis and impact energetic metabolism. Aquaporins (AQPs) are transmembrane channels that facilitate water and glycerol transport across cell membranes and are critical players in energy homeostasis. Altered AQP expression or function impacts fat accumulation and related comorbidities, such as the metabolic syndrome. Here, we sought to determine whether nutritional ketosis impacts AQPs expression in the context of an atherogenic model. To do this, we fed ApoE^−/− (apolipoprotein E-deficient) mice, a model of human atherosclerosis, a KD (Kcal%: 1/81/18, carbohydrate/fat/protein) or a control diet (Kcal%: 70/11/18, carbohydrate/fat/protein) for 12 weeks. Plasma was collected for biochemical analysis. Upon euthanasia, livers, white adipose tissue (WAT), and brown adipose tissue (BAT) were used for gene expression studies. Mice fed the KD and control diets exhibited similar body weights, despite the profoundly different fat contents in the two diets. Moreover, KD-fed mice developed nutritional ketosis and showed increased expression of thermogenic genes in BAT. Additionally, these mice presented an increase in Aqp9 transcripts in BAT, but not in WAT, which suggests the participation of Aqp9 in the influx of excess plasma glycerol to fuel thermogenesis, while the up-regulation of Aqp7 in the liver suggests the involvement of this aquaporin in glycerol influx into hepatocytes. The relationship between nutritional ketosis, energy homeostasis, and the AQP network demands further investigation. Full article

(This article belongs to the Special Issue Cellular Mechanisms of Cardiovascular Disease)

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