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.
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.
|Habibi, Javad; Aroor, Annayya R; Sowers, James R et al. (2017) Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol 16:9|
|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|
|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|
|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|
|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|
|Brown, Scott M; Smith, Cassandra E; Meuth, Alex I et al. (2017) Dipeptidyl Peptidase-4 Inhibition With Saxagliptin Ameliorates Angiotensin II-Induced Cardiac Diastolic Dysfunction in Male Mice. Endocrinology 158:3592-3604|
|Whaley-Connell, Adam; Sowers, James R (2017) Insulin Resistance in Kidney Disease: Is There a Distinct Role Separate from That of Diabetes or Obesity? Cardiorenal Med 8:41-49|
|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|
|Martinez-Lemus, Luis A; Aroor, Annayya R; Ramirez-Perez, Francisco I et al. (2017) Amiloride Improves Endothelial Function and Reduces Vascular Stiffness in Female Mice Fed a Western Diet. Front Physiol 8:456|
|Jia, Guanghong; Sowers, James R (2016) Targeting CITED2 for Angiogenesis in Obesity and Insulin Resistance. Diabetes 65:3535-3536|
Showing the most recent 10 out of 105 publications