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.

中文翻译：

---

替米沙坦通过抑制瘦素自分泌活性和激活PPARγ改善心肌重塑。

高血压左心室肥大（LVH）中负责心肌重塑的机制很复杂。这项研究旨在调查替米沙坦在改善高血压LVH心肌重构中的作用，并探讨替米沙坦对高血压LVH影响的分子机制。八周大的雄性Sprague-Dawley（SD）大鼠通过腹主动脉缩窄建立了高血压LVH。术后六周将替米沙坦灌胃。替米沙坦改善了高血压LVH大鼠的心脏功能障碍和心肌纤维化，并降低了心肌的肾素-血管紧张素-醛固酮系统（RAAS）活性和瘦素水平。为了评估高血压LVH的潜在机制，将心肌成纤维细胞用血管紧张素II（Ang II）或瘦素进行体外处理，加上各种抑制剂。Ang II通过促进AT-1R-ROS-ERK1 / 2途径的AP-1核易位，刺激了心脏成纤维细胞中瘦素的合成和分泌。瘦素通过JAK2 / STAT3途径诱导心脏成纤维细胞胶原代谢异常。替米沙坦通过以自分泌方式抑制局部Ang II诱导的瘦素来改善胶原蛋白代谢紊乱。替米沙坦还通过激活PPAR-γ抑制STAT3磷酸化（瘦素下游信号）来改善Ang II诱导的胶原代谢紊乱。因此，替米沙坦可通过充当AT1R拮抗剂，抑制局部Ang II诱导的瘦素自分泌活性以及充当PPAR-γ激动剂，抑制下游瘦素激活STAT3磷酸化来改善高血压LVH大鼠的心肌重塑。

影响陈述

这项研究显示了高血压LVH大鼠局部心肌RAAS与瘦素之间的串扰。Ang II通过通过促进AT-1R-ROS-ERK1 / 2途径的AP-1核易位，刺激瘦素自分泌活性来诱导心肌重塑；替米沙坦可通过抑制局部Ang II诱导的瘦素自分泌活性和通过激活PPAR-γ抑制瘦素下游信号STAT3磷酸化来改善心肌重塑。这些发现揭示了替米沙坦改善心肌重塑的新分子机制，并可能有助于确定高血压LVH的治疗靶点。