Telmisartan improves myocardial remodeling by inhibiting leptin autocrine activity and activating PPARγ

Abstract

The mechanism responsible for myocardial remodeling in hypertensive left ventricular hypertrophy (LVH) is complex. This study was designed to investigate the role of telmisartan in improving myocardial remodeling in hypertensive LVH and to explore the molecular mechanisms underlying the effects of telmisartan on hypertensive LVH. Hypertensive LVH was established in eight-week-old male Sprague–Dawley (SD) rats by abdominal aortic constriction. Telmisartan was intragastrically administered six weeks after surgery. Telmisartan improved cardiac dysfunction and myocardial fibrosis and reduced myocardial renin-angiotensin-aldosterone system (RAAS) activity and leptin levels in hypertensive LVH rats. To assess the mechanism underlying hypertensive LVH, cardiac fibroblasts were treated in vitro with angiotensin II (Ang II) or leptin, plus various inhibitors. Ang II stimulated leptin synthesis and secretion in cardiac fibroblasts by promoting AP-1 nuclear translocation via the AT1R-ROS-ERK1/2 pathway. Leptin induced collagen metabolism disorder in cardiac fibroblasts via the JAK2/STAT3 pathway. Telmisartan improved collagen metabolism disorder by inhibiting leptin induced by local Ang II in an autocrine manner. Telmisartan also improved Ang II-induced collagen metabolism disorder by inhibiting STAT3 phosphorylation, a leptin downstream signal, by activating PPAR-γ. Telmisartan therefore improved myocardial remodeling in hypertensive LVH rats by acting as an AT1R antagonist, inhibiting leptin autocrine activity induced by local Ang II and by acting as a PPAR-γ agonist, inhibiting downstream leptin activation of STAT3 phosphorylation. These findings indicate the crosstalk between local myocardial RAAS and leptin and suggest a molecular mechanism by which telmisartan improves myocardial remodeling in hypertensive LVH. Impact statement This study shows the crosstalk between local myocardial RAAS and leptin in hypertensive LVH rats; that Ang II induces myocardial remodeling by stimulating leptin autocrine activity by promoting AP-1 nuclear translocation via the AT1R-ROS-ERK1/2 pathway; and that telmisartan improves myocardial remodeling by inhibiting local Ang II-induced leptin autocrine activity and by inhibiting the leptin downstream signal STAT3 phosphorylation by activating PPAR-γ. These findings reveal novel molecular mechanisms by which telmisartan improves myocardial remodeling and could help to identify therapeutic targets for hypertensive LVH.

Effect of Leptin on Chronic Inflammatory Disorders: Insights to Therapeutic Target to Prevent Further Cardiovascular Complication

“…It may lead to cardiac remodeling through triggering its biological and physiological effect using PI3K, mitogen-activated protein kinase (MAPK) and JAK/STAT3 signaling cascade mechanism. 160 However, cardiac hypertrophy may develop because of activation of SNS and renin-angiotensin-aldosterone system. 161 Stangl et al 162 in 2000 carried out a demonstration on mice, and they confirmed that infusion of leptin leads to an increase in sympathetic activity of certain organs.…”

“…167 The induction of leptin signal transduction pathway through PI3K, MAPK, JAK2/STAT3 results in biological and physiological response in different tissues, including left ventricular, which is related to left ventricular hypertrophy (LVH). 160 Moreover, angiotensin II-associated myocardial remodeling may be due to the biological effect of leptin through its signal transduction. 160 In vitro investigation showed that rodent and human cardiomyocyte hyperplasia were activated by the effect of leptin.…”

“…160 Moreover, angiotensin II-associated myocardial remodeling may be due to the biological effect of leptin through its signal transduction. 160 In vitro investigation showed that rodent and human cardiomyocyte hyperplasia were activated by the effect of leptin. 169 Adiposity and obesity are the major risk factors for the pathogenesis of MetS, such as T2DM and hypertension, which in turn leads to cardiovascular complications, 170 because abnormality in adipose tissue and obesity induce a chronic inflammation.…”

Telmisartan Mitigates TNF-α-Induced Type II Collagen Reduction by Upregulating SOX-9

“… 18 Telmisartan suppresses the activity of excessively released Ang-II by inhibiting the binding between Ang-II and its receptor, blocking the process of myocardial hypertrophy and protects against heart failure. 19 Recently, significant inhibitory effects of Telmisartan on MMPs and the degradation of ECM have been widely reported. 20 , 21 In the present study, the protective effect of Telmisartan on TNF-α-induced degradation of ECM in chondrocytes will be investigated to explore the potential therapeutic property of Telmisartan in OA.…”

Hyperleptinemia Results in Systemic Inflammation and the Exacerbation of Ischemia-Reperfusion Myocardial Injury: The Involvement of the JAK/STAT Pathway

“…The expression of leptin receptors on the cardiomyocyte membrane has also been described, suggesting a direct effect of adipokines on myocardial function [2]. Several signalling pathways have been shown to be involved in cardiovascular regulation by leptin, including Janus activated kinase (JAK), signal transducer and activator of transcription 3 (STAT3), mitogen-activated protein (MAP) kinase, and nitric oxide [5], which are associated with a direct hypertrophic effect and can induce cardiac remodelling [2,8]. Continuous short-term leptin infusion following MI in mice causes eccentric left ventricular dilation with increased systolic function [9].…”