Endothelial sodium channel activation promotes cardiac stiffness and diastolic dysfunction in Western diet fed female mice

Sowers, James R.; Habibi, Javad; Jia, Guanghong; Bostick, Brian; Manrique‐Acevedo, Camila; Lastra, Guido; Yang, Yan; Chen, Dongqing; Sun, Zhe; Domeier, Timothy L.; Durante, William; Whaley‐Connell, Adam; Hill, Michael A.; Jaisser, Frédéric; DeMarco, Vincent G.; Aroor, Annayya R.

doi:10.1016/j.metabol.2020.154223

Cited by 14 publications

(13 citation statements)

References 30 publications

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“…In this case, perivisceral fat transforms into a proinflammatory phenotype in a mineralocorticoid receptor-dependent manner ( 649 ). Recent work also implicates increased aldosterone and coronary artery MR activation in promotion of Western diet-induced cardiomyocyte stiffness and diastolic dysfunction ( 650 ).…”

Section: Therapeutic Implications Of Obesity Cardiomyopathymentioning

confidence: 99%

Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications

Ren

Wang

et al. 2021

Physiological Reviews

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The prevalence of heart failure is on the rise and imposes a major health threat, in part, due to the rapidly increased prevalence of overweight and obesity. To this point, epidemiological, clinical and experimental evidence supports the existence of a unique disease entity termed "obesity cardiomyopathy", which develops independent of hypertension, coronary heart disease and other heart diseases. Our contemporary review evaluates the evidence for this pathological condition, examines putative responsible mechanisms, and discusses therapeutic options for this disorder. Clinical findings have consolidated the presence of left ventricular dysfunction in obesity. Experimental investigations have uncovered pathophysiological changes in myocardial structure and function in genetically-predisposed and diet-induced obesity. Indeed, contemporary evidence consolidates a wide array of cellular and molecular mechanisms underlying the etiology of obesity cardiomyopathy including adipose tissue dysfunction, systemic inflammation, metabolic disturbances (insulin resistance, abnormal glucose transport, spillover of free fatty acids, lipotoxicity, and amino acid derangement), altered intracellular especially mitochondrial Ca2+ homeostasis, oxidative stress, autophagy/mitophagy defect, myocardial fibrosis, dampened coronary flow reserve, coronary microvascular disease (microangiopathy), and endothelial impairment. Given the important role of obesity in the increased risk of heart failure, especially that with preserved systolic function and the recent rises in COVID-19-associated cardiovascular mortality, this review should provide compelling evidence for the presence of obesity cardiomyopathy, independent of various comorbid conditions, underlying mechanisms, and offer new insights into potential therapeutic approaches (pharmacological and lifestyle modification) for the clinical management of obesity cardiomyopathy.

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Section: Therapeutic Implications Of Obesity Cardiomyopathymentioning

confidence: 99%

Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications

Ren

Wang

et al. 2021

Physiological Reviews

Self Cite

200

120

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“…IR results in the decreased signaling of the eNOS enzyme and its activation and, therefore, the combination of IR and excessive nutrient supply via excess glucose, sucrose, or fructose will increase mtROS via the electron transport chain to result in EC act and EC dys . Similarly, in manifest T2DM there will be an associated increase in aMt that will leak mtROS—superoxide, and there will be excessive oxidation of the eNOS enzyme cofactor tetrahydrobiopterin (BH4) that ultimately uncouples the eNOS production of NO (eNOS enzyme uncoupling) that will decrease endothelial-derived NO bioavailability [ 11 , 12 , 136 , 140 ]. The endothelial constitutive and rate-limiting enzyme (eNOS) is responsible for the conversion of L-arginine to NO and L-citrulline, and eNOS requires the essential cofactor tetrahydrobiopterin (BH4) [ 12 , 14 , 136 , 140 ].…”

Section: Mets Reloaded and Endothelial Activation (Ec Act ...mentioning

confidence: 99%

“…In physiologic homeostasis, the endothelium is a net producer of NO; however, in obesity, IR, and especially manifest T2DM, the endothelium may become a net producer of superoxide unless the blood glucose is optimally controlled. When the superoxide is excessive, as in T2DM, a decrease in the ratio of NO/ROS develops [ 140 , 141 , 142 , 143 ]. Indeed, reduced endothelial NOS enzyme activity and eNOS uncoupling result in decreased NO bioavailability, and may be considered as the main factor underlying endothelial dysfunction that occurs in the MetS reloaded ( Figure 15 ) [ 14 , 136 , 141 , 142 , 143 ].…”

Section: Mets Reloaded and Endothelial Activation (Ec Act ...mentioning

confidence: 99%

Overview and New Insights into the Metabolic Syndrome: Risk Factors and Emerging Variables in the Development of Type 2 Diabetes and Cerebrocardiovascular Disease

Hayden

2023

Medicina

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Metabolic syndrome (MetS) is considered a metabolic disorder that has been steadily increasing globally and seems to parallel the increasing prevalence of obesity. It consists of a cluster of risk factors which traditionally includes obesity and hyperlipidemia, hyperinsulinemia, hypertension, and hyperglycemia. These four core risk factors are associated with insulin resistance (IR) and, importantly, the MetS is known to increase the risk for developing cerebrocardiovascular disease and type 2 diabetes mellitus. The MetS had its early origins in IR and syndrome X. It has undergone numerous name changes, with additional risk factors and variables being added over the years; however, it has remained as the MetS worldwide for the past three decades. This overview continues to add novel insights to the MetS and suggests that leptin resistance with hyperleptinemia, aberrant mitochondrial stress and reactive oxygen species (ROS), impaired folate-mediated one-carbon metabolism with hyperhomocysteinemia, vascular stiffening, microalbuminuria, and visceral adipose tissues extracellular vesicle exosomes be added to the list of associated variables. Notably, the role of a dysfunctional and activated endothelium and deficient nitric oxide bioavailability along with a dysfunctional and attenuated endothelial glycocalyx, vascular inflammation, systemic metainflammation, and the important role of ROS and reactive species interactome are discussed. With new insights and knowledge regarding the MetS comes the possibility of new findings through further research.

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“…45, 46, 48, 59, 65]. Since 2012, author has observed multiple endothelial (systemic and brain endothelial cell (BEC)) ultrastructural transmission electron microscopic (TEM) remodeling changes (Table 1) [10,13,47,48,49,50,65,136,154,155,156]. ECdys is defined as the decreased synthesis and activity of endothelium-derived nitric oxide (NO), which is frequently referred to as decreased NO bioavailability [65,152].…”

Section: Mets Reloaded and Endothelial Activation (Ecact) And Dysfunc...mentioning

confidence: 99%

Overview and New Insights into the Metabolic Syndrome: Risk Factors and Emerging Variables in the Development of Type 2 Diabetes and Cerebrocardiovascular Disease

Hayden¹

2023

Preprint

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Metabolic syndrome (MetS) is considered a metabolic disorder that has been steadily increasing globally and seems to parallel the increasing prevalence of obesity. It consists of a cluster of risk factors, which traditionally includes obesity and hyperlipidemia, hyperinsulinemia, hypertension, and hyperglycemia. These four core risk factors are associated with insulin resistance (IR) and importantly, the MetS is known to increase the risk for developing cerebrocardiovascular disease and type 2 diabetes mellitus. The MetS had its early origins in IR and syndrome X. It has undergone numerous name changes with additional risk factors and variables being added over the years; however, it still remains the MetS worldwide for the past three decades. This overview continues to add novel insights to the MetS and suggests that leptin resistance with hyperleptinemia, aberrant mitochondrial stress and reactive oxygen species (ROS), impaired folate-mediated one-carbon metabolism with hyperhomocysteinemia, vascular stiffening, microalbuminuria, and visceral adipose tissues extracellular vesicle exosomes be added to the list of associated variables. Notably, the role of a dysfunctional and activated endothelium and deficient nitric oxide bioavailability along with a dysfunctional and attenuated endothelial glycocalyx, vascular inflammation, systemic metainflammation, and the important role ROS and reactive species interactome are discussed. With new insights and knowledge regarding the MetS, comes the possibility of new findings through further research.

show abstract

Endothelial sodium channel activation promotes cardiac stiffness and diastolic dysfunction in Western diet fed female mice

Cited by 14 publications

References 30 publications

Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications

Obesity cardiomyopathy: evidence, mechanisms, and therapeutic implications

Overview and New Insights into the Metabolic Syndrome: Risk Factors and Emerging Variables in the Development of Type 2 Diabetes and Cerebrocardiovascular Disease

Overview and New Insights into the Metabolic Syndrome: Risk Factors and Emerging Variables in the Development of Type 2 Diabetes and Cerebrocardiovascular Disease

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