In my last funded VA merit I proposed to investigate novel molecular mechanisms by which angiotensin II (Ang II), aldosterone and a WD (high in saturated fat and refined carbohydrates individually and collectively promotes insulin (INS) resistance in cardiovascular (CV) and skeletal muscle tissue in male rodents. Because of the increasing awareness by the NIH, the VA, the American Diabetes Association and American Heart Association regarding incorporation of females in research, we performed comparable work in females. We have found that this diet has a more negative CV impact in females. This is of translational relevance to the VA because of increasing numbers of female veterans and because in conditions of INS resistance such as obesity and type 2 diabetes, women display a substantially increased risk for CVD. As the lifetime risk for overweight/obesity and diabetes in women is high, associated CVD in women has become a major health problem. As people become obese and INS resistant, they manifest increasing CV stiffness, an abnormality that tracks closely with increasing CVD. INS resistance in the heart and vasculature results in decreased bioavailable nitric oxide (NO) which is associated with increased CV stiffness. Reduced bioavailable NO results in increased activity of the enzyme transglutaminase 2 (TG2), which increases collagen crosslinking and associated heart and vascular stiffness. We have observed that females, but not males, develop CV stiffness after only 8 weeks of consumption of a WD. Our ongoing work in a female mouse model of INS resistance induced by a WD also demonstrates that mineralocorticoid receptor (MR) blockade improves heart and vascular INS resistance and stiffness. We have garnered evidence that selective knockout of the endothelial cell (EC) MR in female mice abrogates the reduction in CV INS metabolic signaling and CV stiffness and impaired relaxation induced by consumption of a WD for 16 weeks. The role of the ECMR in the genesis of sex-related differences in CV INS signaling and stiffness over time has not been explored. In this proposal, our central hypothesis is that ECMR activation promotes CV INS resistance and stiffness. The corollary to this hypothesis is that impairment in INS metabolic signaling reduces bioavailable NO, which results in extracellular release and activation of TG2 promoting collagen crosslinking and therefore CV stiffness in females and males. In this revised proposal we plan to use a novel rodent model of endothelial specific MR knockout mice fed a WD, as well as innovative techniques to access INS resistance and associated CV stiffness in vivo and ex vivo. In Objective 1, we will determine the role of ECMR-mediated EC stiffening and resultant relationship between impairment of INS metabolic signaling and CV fibrosis/stiffness and impaired relaxation in males and females consuming a WD. relationship between ECMR-mediated impairment of INS metabolic signaling and reduced bioavailable NO and CV stiffness in WD- fed mice. In Objective 2, we will determine the role of ECMR mediated EnNaC activation in promotion of CV INS resistance in relation to vascular and cardiac fibrosis/stiffness and impaired relaxation. We anticipate that results from this proposal will yield unique insights into the mechanisms of CVD in obese and type 2 diabetic Veteran men and women, with the goal of translating these findings into therapeutic strategies to reduce CVD, especially in overweight INS resistant men and women.

Public Health Relevance

Cardiovascular disease (CVD) is a major cause of increased morbidity and mortality in male and female veterans, especially those with diabetes. One early marker for CVD is the process called ?stiffness? of cardiovascular tissue. However, the mechanisms by which environmental factors such as a western diet (high in fat and refined carbohydrates) may promote this stiffness and associated CVD, in obesity and type 2 diabetes are poorly understood and will be studied in proposed research. Understanding the biochemical pathways should contribute to the identification of access points leading to cardiovascular stiffness should lead to specific interventional strategies including new drugs and dietary interventions to prevent CVD in overweight women and men.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Endocriniology A (ENDA)
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Harry S. Truman Memorial VA Hospital
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Jia, Guanghong; Aroor, Annayya R; Hill, Michael A et al. (2018) Role of Renin-Angiotensin-Aldosterone System Activation in Promoting Cardiovascular Fibrosis and Stiffness. Hypertension 72:537-548
Jia, Guanghong; Habibi, Javad; Aroor, Annayya R et al. (2018) Epithelial Sodium Channel in Aldosterone-Induced Endothelium Stiffness and Aortic Dysfunction. Hypertension 72:731-738
Jia, Guanghong; Hill, Michael A; Sowers, James R (2018) Diabetic Cardiomyopathy: An Update of Mechanisms Contributing to This Clinical Entity. Circ Res 122:624-638
Jia, Guanghong; Whaley-Connell, Adam; Sowers, James R (2018) Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia 61:21-28
Manrique-Acevedo, Camila; Ramirez-Perez, Francisco I; Padilla, Jaume et al. (2017) Absence of Endothelial ER? Results in Arterial Remodeling and Decreased Stiffness in Western Diet-Fed Male Mice. Endocrinology 158:1875-1885
Jia, Guanghong; Jia, Yan; Sowers, James R (2017) Role of mineralocorticoid receptor activation in cardiac diastolic dysfunction. Biochim Biophys Acta Mol Basis Dis 1863:2012-2018
Cabandugama, Peminda K; Gardner, Michael J; Sowers, James R (2017) The Renin Angiotensin Aldosterone System in Obesity and Hypertension: Roles in the Cardiorenal Metabolic Syndrome. Med Clin North Am 101:129-137
Aroor, Annayya R; Jia, Guanghong; Habibi, Javad et al. (2017) Uric acid promotes vascular stiffness, maladaptive inflammatory responses and proteinuria in western diet fed mice. Metabolism 74:32-40
Jia, Guanghong; Aroor, Annayya R; Sowers, James R (2017) The role of mineralocorticoid receptor signaling in the cross-talk between adipose tissue and the vascular wall. Cardiovasc Res 113:1055-1063
Aroor, Annayya R; Habibi, Javad; Kandikattu, Hemanth Kumar et al. (2017) Dipeptidyl peptidase-4 (DPP-4) inhibition with linagliptin reduces western diet-induced myocardial TRAF3IP2 expression, inflammation and fibrosis in female mice. Cardiovasc Diabetol 16:61

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