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INTRODUCTION

Diabetic cardiomyopathy (DCM) is predominantly distinguished by impairment in ventricular function and myocardial fibrosis. Previous studies revealed the cardioprotective properties of C1q/tumor necrosis factor-related protein 9 (CTRP9). However, whether CTRP9 affects diabetic myocardial fibrosis and its underlying mechanisms remains unclear.

METHODS

We developed a type 1 diabetes (T1DM) model in CTRP9-KO mice via streptozotocin (STZ) induction to examine cardiac function, histopathology, fibrosis extent, Yes-associated protein (YAP) expression, and the expression of markers for autophagy such LC3-II and p62. Additionally, we analyzed the direct impact of CTRP9 on high glucose (HG)-induced transdifferentiation, autophagic activity, and YAP protein levels in cardiac fibroblasts.

RESULTS

In diabetic mice, CTRP9 expression was decreased in the heart. The absence of CTRP9 aggravated cardiac dysfunction and fibrosis in mice with diabetes, alongside increased YAP expression and impaired autophagy. , HG induced the activation of myocardial fibroblasts, which demonstrated elevated cell proliferation, collagen production, and α-smooth muscle actin (α-SMA) expression. CTRP9 countered these adverse effects by restoring autophagy and reducing YAP protein levels in cardiac fibroblasts. Notably, the protective effects of CTRP9 were negated by the inhibition of autophagy with chloroquine (CQ) or by YAP overexpression through plasmid intervention. Notably, the protective effect of CTRP9 was negated by inhibition of autophagy caused by chloroquine (CQ) or plasmid intervention with YAP overexpression.

DISCUSSION

Our findings suggest that CTRP9 can enhance cardiac function and mitigate cardiac remodeling in DCM through the regulation of YAP-mediated autophagy. CTRP9 holds promise as a potential candidate for pharmacotherapy in managing diabetic cardiac fibrosis.

INTRODUCTION

METHODS

RESULTS

DISCUSSION

引言

糖尿病性心肌病（DCM）主要表现为心室功能受损和心肌纤维化。先前的研究揭示了C1q/肿瘤坏死因子相关蛋白9（CTRP9）的心脏保护特性。然而，CTRP9是否影响糖尿病心肌纤维化及其潜在机制仍不清楚。

方法

我们通过链脲佐菌素（STZ）诱导在CTRP9基因敲除（KO）小鼠中建立1型糖尿病（T1DM）模型，以检测心脏功能、组织病理学、纤维化程度、Yes相关蛋白（YAP）表达以及自噬标志物如LC3-II和p62的表达。此外，我们分析了CTRP9对高糖（HG）诱导的心脏成纤维细胞转分化、自噬活性和YAP蛋白水平的直接影响。

结果

在糖尿病小鼠中，心脏中CTRP9表达降低。CTRP9缺失加重了糖尿病小鼠的心脏功能障碍和纤维化，同时YAP表达增加且自噬受损。HG诱导心肌成纤维细胞活化，表现为细胞增殖、胶原蛋白产生和α平滑肌肌动蛋白（α-SMA）表达升高。CTRP9通过恢复自噬和降低心脏成纤维细胞中的YAP蛋白水平来对抗这些不良反应。值得注意的是，氯喹（CQ）抑制自噬或通过质粒干预过表达YAP可抵消CTRP9的保护作用。值得注意的是，氯喹（CQ）抑制自噬或质粒干预过表达YAP可抵消CTRP9的保护作用。