Molecular Mechanisms of Adiponectin-Induced Attenuation of Mechanical Stretch-Mediated Vascular Remodeling

Abstract

Hypertension induces vascular hypertrophy, which changes blood vessels structurally and functionally, leading to reduced tissue perfusion and further hypertension. It is also associated with dysregulated levels of the circulating adipokines leptin and adiponectin (APN). Leptin is an obesity-associated hormone that promotes vascular smooth muscle cell (VSMC) hypertrophy. APN is a cardioprotective hormone that has been shown to attenuate hypertrophic cardiomyopathy. In this study, we investigated the molecular mechanisms of hypertension-induced VSMC remodeling and the involvement of leptin and APN in this process. To mimic hypertension, the rat portal vein (RPV) was mechanically stretched, and the protective effects of APN on mechanical stretch-induced vascular remodeling and the molecular mechanisms involved were examined by using 10 μg/ml APN. Mechanically stretching the RPV significantly decreased APN protein expression after 24 hours and APN mRNA expression in a time-dependent manner in VSMCs. The mRNA expression of the APN receptors AdipoR1, AdipoR2, and T-cadherin significantly increased after 15 hours of stretch. The ratio of APN/leptin expression in VSMCs significantly decreased after 24 hours of mechanical stretch. Stretching the RPV for 3 days increased the weight and [3H]-leucine incorporation significantly, whereas APN significantly reduced hypertrophy in mechanically stretched vessels. Stretching the RPV for 10 minutes significantly decreased phosphorylation of LKB1, AMPK, and eNOS, while APN significantly increased p-LKB1, p-AMPK, and p-eNOS in stretched vessels. Mechanical stretch significantly increased p-ERK1/2 after 10 minutes, whereas APN significantly reduced stretch-induced ERK1/2 phosphorylation. Stretching the RPV also significantly increased ROS generation after 1 hour, whereas APN significantly decreased mechanical stretch-induced ROS production. Exogenous leptin (3.1 nM) markedly increased GATA-4 nuclear translocation in VSMCs, whereas APN significantly attenuated leptin-induced GATA-4 nuclear translocation. Our results decipher molecular mechanisms of APN-induced attenuation of mechanical stretch-mediated vascular hypertrophy, with the promising potential of ultimately translating this protective hormone into the clinic.

Between Inflammation and Autophagy: The Role of Leptin-Adiponectin Axis in Cardiac Remodeling

“…MiR-22 has been reported as a crucial modulator of the expression of genes involved in cardiac hypertrophy, actin cytoskeleton reorganization, and metabolic pathways leading to cardiovascular remodeling. 4 During cardiac remodeling, changes occur in the calcium transport system; these include a decrease in L-type calcium channels, calsequestrin and calmodulin kinase activity, and phospholamban phosphorylation, leading to reduced calcium supply during cardiac contraction and increased supply during diastole. Consequently, the modifications in the calcium transit proteins may contribute to cardiac dysfunction.…”

“…28 Adiponectin has been shown to attenuate overload-induced and adrenergically-induced cardiomyocyte hypertrophy in mice by inhibiting hypertrophic signaling pathways via AMPK. 4 Therefore, the downregulated levels of this adipokine in obesity are linked to increased cardiac risk in at least 2 ways: Myocardial insult and inflammation-induced cardiovascular insufficiency. [100]…”

“…MiR-22 has been reported as a crucial modulator of the expression of genes involved in cardiac hypertrophy, actin cytoskeleton reorganization, and metabolic pathways leading to cardiovascular remodeling. 4 …”

“… 3 The ability of the cardiac muscle to sense and respond to mechanical stretch occurs through a process known as mechanotransduction, which is the conversion of mechanical triggers into biochemical incidents. 4 This, in turn, causes a change in myocardial function and structure as a compensatory mechanism during adaptation to the trigger. 5 In the case of prolonged stimuli, signal transduction occurs and the whole process becomes maladaptive, causing a change in the physiology of the heart, and subsequently leading to development of cardiac remodeling/hypertrophy.…”

Cardiovascular Health, Testosterone, and Oxandrolone: Leveraging the Myotrophic-Androgenic Ratio in Males with a Sarcopenic Obese Phenotype

“…The obesity in sarcopenia has been observed to promote a status of inflammation that results in dysregulation of normal adipocyte regulation, resulting in ectopic lipid deposition in myocytes causing lipotoxicity via impairment of mitochondrial β-oxidation, insulin regulation, and the promotion of ROS, exacerbating the release of deleterious myokines that further decreases skeletal muscle mass and the concomitant cardiovascular impairments associated with them [60]. In healthy conditions, adipose tissue secretes adiponectin, an adipokine responsible for the stimulation of 5ʹ-AMP-Activated Protein Kinase (AMPK) leading to endothelial synthase (eNOS) function [61]. Moreover, adiponectin has been shown to promote hydrogen sulfide H 2 S production, a known modulator of voltagegated potassium channels [62].…”