International Journal of Molecular Sciences

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Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets

by Iveta Bernatova and Monika Bartekova

Int. J. Mol. Sci. 2024, 25(11), 5841; https://doi.org/10.3390/ijms25115841 - 27 May 2024

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Abstract

Cardiometabolic diseases (CMDs) encompass a range of prevalent, often preventable, non-communicable illnesses, including myocardial infarction, stroke, cardiac insufficiency, arterial hypertension, obesity, type 2 diabetes mellitus, insulin resistance, chronic renal dysfunction, non-alcoholic fatty liver disease, and rare metabolic disorders [...] Full article

(This article belongs to the Special Issue Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets)

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21 pages, 4102 KiB

Open AccessArticle

Ketogenic Diet Regulates Cardiac Remodeling and Calcium Homeostasis in Diabetic Rat Cardiomyopathy

by Ting-I Lee, Nguyen Ngoc Trang, Ting-Wei Lee, Satoshi Higa, Yu-Hsun Kao, Yao-Chang Chen and Yi-Jen Chen

Int. J. Mol. Sci. 2023, 24(22), 16142; https://doi.org/10.3390/ijms242216142 - 9 Nov 2023

Cited by 3 | Viewed by 1956

Abstract

A ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis are closely linked to calcium (Ca²⁺) homeostasis. We investigated the effects of a KD on Ca²⁺ homeostasis and electrophysiology in [...] Read more.

A ketogenic diet (KD) might alleviate patients with diabetic cardiomyopathy. However, the underlying mechanism remains unclear. Myocardial function and arrhythmogenesis are closely linked to calcium (Ca²⁺) homeostasis. We investigated the effects of a KD on Ca²⁺ homeostasis and electrophysiology in diabetic cardiomyopathy. Male Wistar rats were created to have diabetes mellitus (DM) using streptozotocin (65 mg/kg, intraperitoneally), and subsequently treated for 6 weeks with either a normal diet (ND) or a KD. Our electrophysiological and Western blot analyses assessed myocardial Ca²⁺ homeostasis in ventricular preparations in vivo. Unlike those on the KD, DM rats treated with an ND exhibited a prolonged QTc interval and action potential duration. Compared to the control and DM rats on the KD, DM rats treated with an ND also showed lower intracellular Ca²⁺ transients, sarcoplasmic reticular Ca²⁺ content, sodium (Na⁺)-Ca²⁺ exchanger currents (reverse mode), L-type Ca²⁺ contents, sarcoplasmic reticulum ATPase contents, Cav1.2 contents. Furthermore, these rats exhibited elevated ratios of phosphorylated to total proteins across multiple Ca²⁺ handling proteins, including ryanodine receptor 2 (RyR2) at serine 2808, phospholamban (PLB)-Ser16, and calmodulin-dependent protein kinase II (CaMKII). Additionally, DM rats treated with an ND demonstrated a higher frequency and incidence of Ca²⁺ leak, cytosolic reactive oxygen species, Na⁺/hydrogen-exchanger currents, and late Na⁺ currents than the control and DM rats on the KD. KD treatment may attenuate the effects of DM-dysregulated Na⁺ and Ca²⁺ homeostasis, contributing to its cardioprotection in DM. Full article

(This article belongs to the Special Issue Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets)

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16 pages, 3501 KiB

Open AccessArticle

Taxifolin Reduces Blood Pressure via Improvement of Vascular Function and Mitigating the Vascular Inflammatory Response in Spontaneously Hypertensive Rats

by Silvia Liskova, Sona Cacanyiova, Martina Cebova, Andrea Berenyiova, Michal Kluknavsky, Andrea Micurova, Katarina Valachova, Ladislav Soltes and Iveta Bernatova

Int. J. Mol. Sci. 2023, 24(16), 12616; https://doi.org/10.3390/ijms241612616 - 9 Aug 2023

Cited by 7 | Viewed by 1870

Abstract

The effect of a 10-day-long treatment with taxifolin (TAX, 20 mg/kg/day p.o.) was investigated on spontaneously hypertensive rats (SHRs) with a focus on the vascular functions of isolated femoral arteries and thoracic aortas. TAX reduced blood pressure in SHRs. In femoral arteries, TAX [...] Read more.

The effect of a 10-day-long treatment with taxifolin (TAX, 20 mg/kg/day p.o.) was investigated on spontaneously hypertensive rats (SHRs) with a focus on the vascular functions of isolated femoral arteries and thoracic aortas. TAX reduced blood pressure in SHRs. In femoral arteries, TAX increased acetylcholine-induced relaxation, reduced the maximal NA-induced contraction, and reduced acetylcholine-induced endothelium-dependent contraction (EDC); however, TAX had no effect on the vascular reactivity of isolated thoracic aortas. In addition, TAX elevated the total nitric oxide synthase (NOS) activity and iNOS protein expression but reduced cyclooxygenase-2 (COX2) protein expression in the tissue of the abdominal aorta without changes in Nos2 and Ptgs2 gene expressions. TAX also increased the gene expression of the anti-inflammatory interleukin-10 (Il10). In addition, in vitro studies showed that TAX has both electron donor and H atom donor properties. However, TAX failed to reduce superoxide production in the tissue of the abdominal aorta after oral administration. In conclusion, our results show that a decrease in the blood pressure in TAX-treated SHRs might be attributed to improved endothelium-dependent relaxation and reduced endothelium-dependent contraction. In addition, the results suggest that the effect of TAX on blood pressure regulation also involves the attenuation of COX2-mediated pro-inflammation and elevation of anti-inflammatory pathways. Full article

(This article belongs to the Special Issue Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets)

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18 pages, 7460 KiB

Open AccessArticle

Untargeted Lipidomic Profiling Reveals Lysophosphatidylcholine and Ceramide as Atherosclerotic Risk Factors in apolipoprotein E Knockout Mice

by Shi-Hui Law, Hua-Chen Chan, Guan-Ming Ke, Swetha Kamatam, Gopal Kedihithlu Marathe, Vinoth Kumar Ponnusamy and Liang-Yin Ke

Int. J. Mol. Sci. 2023, 24(8), 6956; https://doi.org/10.3390/ijms24086956 - 9 Apr 2023

Cited by 5 | Viewed by 2628

Abstract

Despite the availability and use of numerous cholesterol-lowering drugs, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality globally. Many researchers have focused their effort on identifying modified lipoproteins. However, lipid moieties such as lysophosphatidylcholine (LPC) and ceramide (CER) contribute to atherogenic [...] Read more.

Despite the availability and use of numerous cholesterol-lowering drugs, atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality globally. Many researchers have focused their effort on identifying modified lipoproteins. However, lipid moieties such as lysophosphatidylcholine (LPC) and ceramide (CER) contribute to atherogenic events. LPC and CER both cause endothelial mitochondrial dysfunction, leading to fatty acid and triglyceride (TG) accumulation. In addition, they cause immune cells to differentiate into proinflammatory phenotypes. To uncover alternative therapeutic approaches other than cholesterol- and TG-lowering medications, we conducted untargeted lipidomic investigations to assess the alteration of lipid profiles in apolipoprotein E knockout (apoE^−/−) mouse model, with or without feeding a high-fat diet (HFD). Results indicated that, in addition to hypercholesterolemia and hyperlipidemia, LPC levels were two to four times higher in apoE^−/− mice compared to wild-type mice in C57BL/6 background, regardless of whether they were 8 or 16 weeks old. Sphingomyelin (SM) and CER were elevated three- to five-fold in apoE^−/− mice both at the basal level and after 16 weeks when compared to wild-type mice. After HFD treatment, the difference in CER levels elevated more than ten-fold. Considering the atherogenic properties of LPC and CER, they may also contribute to the early onset of atherosclerosis in apoE^−/− mice. In summary, the HFD-fed apoE^−/− mouse shows elevated LPC and CER contents and is a suitable model for developing LPC- and CER-lowering therapies. Full article

(This article belongs to the Special Issue Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets)

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Review

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17 pages, 1705 KiB

Open AccessReview

Exploring the Role of Bempedoic Acid in Metabolic Dysfunction Associated Steatotic Liver Disease: Actual Evidence and Future Perspectives

by Elena Butera, Fabrizio Termite, Giorgio Esposto, Linda Galasso, Irene Mignini, Raffaele Borriello, Maria Elena Ainora, Luca Miele, Antonio Gasbarrini and Maria Assunta Zocco

Int. J. Mol. Sci. 2024, 25(13), 6938; https://doi.org/10.3390/ijms25136938 - 25 Jun 2024

Cited by 1 | Viewed by 1635

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression to severe liver conditions. Its pathogenesis involves genetic, metabolic, and inflammatory factors, with cardiovascular events as the leading cause [...] Read more.

Metabolic dysfunction-associated steatotic liver disease (MASLD) involves excessive lipid accumulation in hepatocytes, impacting global healthcare due to its high prevalence and risk of progression to severe liver conditions. Its pathogenesis involves genetic, metabolic, and inflammatory factors, with cardiovascular events as the leading cause of mortality. This review examines the role of lipid-lowering therapies in MASLD, with a particular focus on bempedoic acid, a recently approved cholesterol-lowering agent for hypercholesterolemia and high cardiovascular-risk patients. It explores its potential in liver disease by modulating lipid metabolism and inflammatory pathways based on the most recent studies available. Bempedoic acid inhibits ATP-citrate lyase, reducing cholesterol and fatty acid synthesis while activating AMP-activated protein kinase to suppress gluconeogenesis and lipogenesis. Animal studies indicate its efficacy in reducing hepatic steatosis, inflammation, and fibrosis. Bempedoic acid holds promise as a therapeutic for MASLD, offering dual benefits in lipid metabolism and inflammation. Further clinical trials are required to confirm its efficacy and safety in MASLD patients, potentially addressing the multifaceted nature of this disease. Full article

(This article belongs to the Special Issue Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets)

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27 pages, 1960 KiB

Open AccessReview

Sexual Dimorphism in Cardiometabolic Diseases: The Role of AMPK

by Miroslava Kvandova, Angelika Puzserova and Peter Balis

Int. J. Mol. Sci. 2023, 24(15), 11986; https://doi.org/10.3390/ijms241511986 - 26 Jul 2023

Cited by 1 | Viewed by 1688

Abstract

Cardiovascular diseases (CVDs) are the leading cause of mortality and disability among both males and females. The risk of cardiovascular diseases is heightened by the presence of a risk factor cluster of metabolic syndrome, covering obesity and obesity-related cardiometabolic risk factors such as [...] Read more.

Cardiovascular diseases (CVDs) are the leading cause of mortality and disability among both males and females. The risk of cardiovascular diseases is heightened by the presence of a risk factor cluster of metabolic syndrome, covering obesity and obesity-related cardiometabolic risk factors such as hypertension, glucose, and lipid metabolism dysregulation primarily. Sex hormones contribute to metabolic regulation and make women and men susceptible to obesity development in a different manner, which necessitates sex-specific management. Identifying crucial factors that protect the cardiovascular system is essential to enhance primary and secondary prevention of cardiovascular diseases and should be explicitly studied from the perspective of sex differences. It seems that AMP-dependent protein kinase (AMPK) may be such a factor since it has the protective role of AMPK in the cardiovascular system, has anti-diabetic properties, and is regulated by sex hormones. Those findings highlight the potential cardiometabolic benefits of AMPK, making it an essential factor to consider. Here, we review information about the cross-talk between AMPK and sex hormones as a critical point in cardiometabolic disease development and progression and a target for therapeutic intervention in human disease. Full article

(This article belongs to the Special Issue Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets)

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18 pages, 851 KiB

Open AccessReview

Benefits of Biotics for Cardiovascular Diseases

by Emília Hijová

Int. J. Mol. Sci. 2023, 24(7), 6292; https://doi.org/10.3390/ijms24076292 - 27 Mar 2023

Cited by 7 | Viewed by 3047

Abstract

Cardiovascular diseases are the main cause of death in many countries, and the better prevention and prediction of these diseases would be of great importance for individuals and society. Nutrition, the gut microbiota, and metabolism have raised much interest in the field of [...] Read more.

Cardiovascular diseases are the main cause of death in many countries, and the better prevention and prediction of these diseases would be of great importance for individuals and society. Nutrition, the gut microbiota, and metabolism have raised much interest in the field of cardiovascular disease research in the search for the main mechanisms that promote cardiovascular diseases. Understanding the interactions between dietary nutrient intake and the gut microbiota-mediated metabolism may provide clinical insight in order to identify individuals at risk of cardiometabolic disease progression, as well as other potential therapeutic targets to mitigate the risk of cardiometabolic disease progression. The development of cardiometabolic diseases can be modulated by specific beneficial metabolites derived from bacteria. Therefore, it is very important to investigate the impact of these metabolites on human health and the possibilities of modulating their production with dietary supplements called biotics. Full article

(This article belongs to the Special Issue Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets)

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31 pages, 963 KiB

Open AccessReview

Molecular Mechanisms and Therapeutic Implications of Endothelial Dysfunction in Patients with Heart Failure

by Vasiliki Tsigkou, Evangelos Oikonomou, Artemis Anastasiou, Stamatios Lampsas, George E. Zakynthinos, Konstantinos Kalogeras, Maria Katsioupa, Maria Kapsali, Islam Kourampi, Theodoros Pesiridis, Georgios Marinos, Michael-Andrew Vavuranakis, Dimitris Tousoulis, Manolis Vavuranakis and Gerasimos Siasos

Int. J. Mol. Sci. 2023, 24(5), 4321; https://doi.org/10.3390/ijms24054321 - 21 Feb 2023

Cited by 19 | Viewed by 6358

Abstract

Heart failure is a complex medical syndrome that is attributed to a number of risk factors; nevertheless, its clinical presentation is quite similar among the different etiologies. Heart failure displays a rapidly increasing prevalence due to the aging of the population and the [...] Read more.

Heart failure is a complex medical syndrome that is attributed to a number of risk factors; nevertheless, its clinical presentation is quite similar among the different etiologies. Heart failure displays a rapidly increasing prevalence due to the aging of the population and the success of medical treatment and devices. The pathophysiology of heart failure comprises several mechanisms, such as activation of neurohormonal systems, oxidative stress, dysfunctional calcium handling, impaired energy utilization, mitochondrial dysfunction, and inflammation, which are also implicated in the development of endothelial dysfunction. Heart failure with reduced ejection fraction is usually the result of myocardial loss, which progressively ends in myocardial remodeling. On the other hand, heart failure with preserved ejection fraction is common in patients with comorbidities such as diabetes mellitus, obesity, and hypertension, which trigger the creation of a micro-environment of chronic, ongoing inflammation. Interestingly, endothelial dysfunction of both peripheral vessels and coronary epicardial vessels and microcirculation is a common characteristic of both categories of heart failure and has been associated with worse cardiovascular outcomes. Indeed, exercise training and several heart failure drug categories display favorable effects against endothelial dysfunction apart from their established direct myocardial benefit. Full article

(This article belongs to the Special Issue Molecular Aspects of Cardiometabolic Diseases: From Etiopathogenesis to Potential Therapeutic Targets)

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