Diminished insulin (INS) sensitivity is a common feature of disease states such as obesity, hypertension and diabetes. Over-nutrition (especially that characterized by excess intake of fat and carbohydrates) is a major factor in the increased prevalence of hypertension and diabetes. These co-morbidities may be driven by a decrease in INS-mediated vasorelaxation and glucose transport in cardiovascular (CV) and skeletal muscle tissue. In addition to over-nutrition, several other mechanisms, such as enhanced activation of the renin- angiotensin-system (RAS), inflammation, and associated abnormalities in INS metabolic signaling, may help explain the linkage between INS resistance and hypertension. There is emerging evidence that over-nutrition and angiotensin II (ANG II) may promote INS resistance through the mammalian target of rapamycin (mTOR)/S6 kinase 1 (S6K1) signaling pathway. mTOR, a highly conserved nutrient sensor, modulates INS metabolic signaling through its phosphorylation (P) of S6K1, an evolutionarily conserved serine (Ser) kinase. Evidence is mounting that chronic activation of S6K1, by excessive nutrients, promotes INS resistance in fat, liver and skeletal muscle tissue through increased Ser (P) of the critical INS signaling/docking molecule, INS receptor substrate protein 1 (IRS-1), leading to impaired phosphoinositol 3 kinase (PI3-K) engagement and protein kinase B (Akt) stimulation. Our recent work indicates that S6K1 is activated by ANG II in CV tissue leading to diminished INS metabolic signaling and biological consequences, such as impaired nitric oxide (NO)-mediated vascular relaxation. This proposal seeks to investigate novel molecular mechanisms by which ANG II and over-nutrition individually and collectively promote INS resistance in CV and skeletal muscle tissue. To evaluate the CV functional effects of INS metabolic signaling, we will utilize our state of the art rodent imaging center. In the INS resistant state, myocardial and skeletal muscle glucose uptake and metabolism is impaired, leading to diastolic dysfunction, attenuated myocardial and skeletal muscle blood flow, and impaired ischemic reconditioning. We have shown that both impaired INS stimulated glucose uptake and diastolic dysfunction are related to impaired systemic and myocardial INS metabolic signaling in models of obesity and increased tissue RAS expression. For this proposal, we will utilize novel knockout and knockdown strategies, as well as innovative rodent imaging tools, to evaluate the impact of increased S6K1 signaling (ANG II and/or excess nutrients) on myocardial function and coronary and skeletal microvascular blood flow responses to INS metabolic signaling. To address Aim 1, we will examine the relationship between ANG II and S6K1 activation and INS signaling in primary cultured endothelial cells, vascular smooth muscle cells and cardiomyocytes. Metabolic signaling results will be correlated to functional measures including NO production, cardiomyocyte glucose transport and diastolic relaxation. To further explore the collective, as well as the independent, roles of ANG II and over-nutrition on S6K1, Aim 2 will focus on in vivo/ex vivo effects in the S6K1-/- and C57BL/6 mice treated with ANG II that produces a slow pressor response and/or a high fat (60%) and high sucrose (20%) diet. A cohort of animals will be treated with an AT1R blocker (olmesartan) at a dose of 0.5 mg/kg/day, a dose determined by telemetry to have no effect on blood pressure in db/db mice. INS resistance will be assessed by hyperinsulinemic, euglycemic clamp, cardiac PET scanning, ex vivo IRS-1 (P) and INS metabolic signaling, and glucose uptake in heart and skeletal muscle. Finally, in vivo INS mediated skeletal muscle arteriolar and ex vivo coronary arteriolar, NO induced relaxation, and in vivo cardiac glucose uptake and diastolic relaxation will be related to ex vivo S6K1 activity and IRS-1 site specific Ser vs. Tyr (P) and the resultant downstream IRS-1/PI3-K/Akt signaling.

Public Health Relevance

Insulin is critical for normal cardiovascular function as well as maintaining normal blood glucose levels. Tissue resistance to the normal metabolic actions of insulin is often present in persons with hypertension and is a precursor for type 2 diabetes mellitus and cardiovascular disease. The fundamental mechanisms underlying insulin resistance in cardiovascular tissue, as well as skeletal muscle, are not well understood and our proposed work is directed at elucidation of this abnormity. A better understanding of factors involved in insulin resistance should help in the development of therapeutic targets to help prevent diabetes and cardiovascular disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Ershow, Abby
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Missouri-Columbia
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
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
Zhang, Yingmei; Whaley-Connell, Adam T; Sowers, James R et al. (2018) Autophagy as an emerging target in cardiorenal metabolic disease: From pathophysiology to management. Pharmacol Ther 191:1-22
Ren, Jun; Sowers, James R; Zhang, Yingmei (2018) Metabolic Stress, Autophagy, and Cardiovascular Aging: from Pathophysiology to Therapeutics. Trends Endocrinol Metab 29:699-711
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
Jia, Guanghong; Habibi, Javad; Aroor, Annayya R et al. (2018) Enhanced endothelium epithelial sodium channel signaling prompts left ventricular diastolic dysfunction in obese female mice. Metabolism 78:69-79
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

Showing the most recent 10 out of 113 publications