FP-receptor gene silencing ameliorates myocardial fibrosis and protects from diabetic cardiomyopathy
FP-receptor gene silencing ameliorates myocardial fibrosis and protects from diabetic cardiomyopathy
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FP受体基因沉默可改善心肌纤维化并预防糖尿病心肌病
DOI：
10.1007/s00109-013-1119-9
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发表时间：
2014-06-01
影响因子：
4.7
通讯作者：
Zhang, Wei
中科院分区：
文献类型：
--
作者：
Ding, Wen-yuan;Liu, Lin;Zhang, Wei
前列腺素F2（alpha）-F-前列腺素（PGF 2（alpha）-FP）受体与胰岛素抵抗密切相关，胰岛素抵抗在糖尿病心肌病（DCM）的发病中起重要作用。我们试图揭示PGF 2（α）-FP受体是否在DCM的调节中起重要作用及其机制。采用高脂饮食和小剂量链脲佐菌素（STZ）建立2型糖尿病大鼠模型，通过代谢物检测、FP受体蛋白表达的Western blot分析、心肌细胞密度和纤维化面积的组织病理学分析，评价其特点。接下来，我们使用基因沉默来研究FP受体在DCM病理生理学特征中的作用。我们的研究显示糖尿病大鼠胆固醇、甘油三酯、葡萄糖和胰岛素水平升高，严重的胰岛素抵抗和FP受体过表达。糖尿病组胶原体积分数（CVF）和血管周围胶原面积/管腔面积（PVCA/LA）均高于对照组（CVF% 10.99 ± 0.99 vs 1.59 ± 0.18，P < 0.05; PVCA/LA% 17.07 ± 2.61 vs 2.86 ± 0.69，P < 0.05）。我们发现FP受体的沉默降低了胆固醇、甘油三酯、葡萄糖和胰岛素水平，改善了胰岛素抵抗。FP-receptor短发夹RNA（shRNA）治疗组CVF和PVCF/LA显著下调（FP-受体shRNA组与载体组：CVF% 5.59 +/- 0.92 vs 10.97 +/- 1.33，P < 0.05，PVCA/LA% 4.74 +/- 1.57 vs 14.79 +/- 2.22，P < 0.05; FP-受体shRNA + PGF 2（α）组与媒介物组：分别为CVF% 5.19 +/- 0.79 vs 10.97 +/- 1.33，P < 0.05，PVCA/LA% 5.96 +/- 1.15 vs 14.79 +/- 2.22，P < 0.05）。此外，FP受体基因沉默，激活的蛋白激酶C（PKC）和Rho激酶显着减少，并恢复Akt的钝化磷酸化。FP-受体基因沉默可能通过改善心肌纤维化对DCM发挥保护作用，为DCM的治疗提供了新的途径。
Prostaglandin F2(alpha)-F-prostanoid (PGF2(alpha)-FP) receptor is closely related to insulin resistance, which plays a causal role in the pathogenesis of diabetic cardiomyopathy (DCM). We sought to reveal whether PGF2(alpha)-FP receptor plays an important part in modulating DCM and the mechanisms involved. We established the type 2 diabetes rat model by high-fat diet and low-dose streptozotocin (STZ) and then evaluated its characteristics by metabolite tests, Western blot analysis for FP-receptor expression, histopathologic analyses of cardiomyocyte density and fibrosis area. Next, we used gene silencing to investigate the role of FP receptor in the pathophysiologic features of DCM. Our study showed elevated cholesterol, triglyceride, glucose, and insulin levels, severe insulin resistance, and FP-receptor overexpression in diabetic rats. The collagen volume fraction (CVF) and perivascular collagen area/luminal area (PVCA/LA) were higher in the diabetic group than the control group (CVF% 10.99 +/- 0.99 vs 1.59 +/- 0.18, P < 0.05; PVCA/LA% 17.07 +/- 2.61 vs 2.86 +/- 0.69, P < 0.05). We found that the silencing of FP receptor decreased cholesterol, triglyceride, glucose, and insulin levels and ameliorated insulin resistance. The CVF and PVCF/LA were significantly downregulated in FP-receptor short hairpin RNA (shRNA) treatment group (FP-receptor shRNA group vs vehicle group: CVF% 5.59 +/- 0.92 vs 10.97 +/- 1.33, P < 0.05, PVCA/LA% 4.74 +/- 1.57 vs 14.79 +/- 2.22, P < 0.05; FP-receptor shRNA + PGF2(alpha) group vs vehicle group : CVF% 5.19 +/- 0.79 vs 10.97 +/- 1.33, P < 0.05, PVCA/LA% 5.96 +/- 1.15 vs 14.79 +/- 2.22, P < 0.05, respectively). Furthermore, with FP-receptor gene silencing, the activated protein kinase C (PKC) and Rho kinase were significantly decreased, and the blunted phosphorylation of Akt was restored. FP-receptor gene silencing may exert a protective effect on DCM by improving myocardial fibrosis, suggesting a new therapeutic approach for human DCM.