Adaptive mechanisms to compensate for overnutrition-induced cardiovascular abnormalities

Abstract

In conditions of overnutrition, cardiac cells must cope with a multitude of extracellular signals generated by changes in nutrient load (glucose, amino acids, and lipids) and the hormonal milieu [increased insulin (INS), ANG II, and adverse cytokine/adipokine profile]. Herein, we review the diverse compensatory/adaptive mechanisms that counter the deleterious effects of excess nutrients and growth factors. We largely focus the discussion on evidence obtained from Zucker obese (ZO) and Zucker diabetic fatty (ZDF) rats, which are useful models to evaluate adaptive and maladaptive metabolic, structural, and functional cardiac remodeling. One adaptive mechanism present in the INS-resistant ZO, but absent in the diabetic ZDF heart, involves an interaction between the nutrient sensor kinase mammalian target of rapamycin complex 1 (mTORC1) and ANG II-type 2 receptor (AT2R). Recent evidence supports a cardioprotective role for the AT2R; for example, suppression of AT2R activation interferes with antihypertrophic/antifibrotic effects of AT1R blockade, and AT2R agonism improves cardiac structure and function. We propose a scenario, whereby mTORC1-signaling-mediated increase in AT2R expression in the INS-resistant ZO heart is a cardioprotective adaptation to overnutrition. In contrast to the ZO rat, heart tissues of ZDF rats do not show activation of mTORC1. We posit that such a lack of activation of the mTOR↔AT2R integrative pathway in cardiac tissue under conditions of obesity-induced diabetes may be a metabolic switch associated with INS deficiency and clinical diabetes.

Overnutrition, mTOR signaling, and cardiovascular diseases

“…Interestingly, hyperinsulinemia-induced cardiac hypertrophy is accompanied by a reduction in AT 1 R, an increase in AT 2 R, and activation of S6K1 via the PI3K/Akt signaling pathway (61). The association between increases in AT 2 R protein and mTOR/S6K1 activation in insulin resistance-induced cardiac hypertrophy prompts us to posit that mTOR/S6K1-induced increases in translation could, in part, contribute to increases in AT 2 R protein levels (60).…”

“…Increased mTORC1-mediated translation underlies cardiac hypertrophy and is implicated in cardiovascular dysfunction. Meanwhile, cardiac overexpression of mTOR protects against cardiac dysfunction following left ventricular pressure overload through activation of AT 2 R, which provides a downstream cardioprotective compensatory servoregulatory mechanism (61).…”

“…For example, mice consuming a WD manifest activation of immune cellular components, including granulocytes, mast cells, monocytes, macrophages, dendritic cells, and natural killer cells (81), and display increased heart and vascular fibrosis leading to left ventricular hypertrophy (LVH), myocardial diastolic dysfunction, and vascular stiffness (87). Indeed, impaired insulin metabolic signaling in cardiovascular tissues may explain the link between obesity, hypertension, LVH, cardiac and vascular stiffness, and associated increases in CVD risk (48,61,70).…”

Mitochondria and Oxidative Stress in the Cardiorenal Metabolic Syndrome

“…We have previously proposed that compensative/adaptive mechanisms are activated in ZO rat heart that may have a role in attenuating the progression to diabetic cardiomyopathy in these animals compared to Zucker diabetic fatty rats [175] . Additionally, we have recently shown that miR-200c, an miRNA only modestly expressed in the heart, is increased in ZO rat heart, and this increase in miR-200c may serve as a compensatory mechanism to downregulate excessive activation of the nutrient sensor kinase S6K1 [176] .…”

Prehypertension: Underlying pathology and therapeutic options

“…ACE2 have been described to be a potent negative regulator of RAS, counterbalancing the multiple functions of ACE, thus, it plays a protective role in the CV system and other organs [75] . Also, chronic activation of the RAS was shown to underlie HTN, insulin resistance, cardiac and renal disease, and polycystic ovarian syndrome and it serves as a link between obesity and low-grade systematic inflammation [76][77][78][79][80] . In addition, it is suggested that RAS contributes to the atherosclerotic process through angiotensin Ⅱ, which acts as a proinflammatory mediator directly inducing atherosclerotic plaque development and heart remodeling and exacerbate endothelial dysfunction [81,82] .…”