STK35 Gene Therapy Attenuates Endothelial Dysfunction and Improves Cardiac Function in Diabetes.
STK35 Gene Therapy Attenuates Endothelial Dysfunction and Improves Cardiac Function in Diabetes.
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DOI：
10.3389/fcvm.2021.798091
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发表时间：
2021
影响因子：
3.6
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Joladarashi D;Zhu Y;Willman M;Nash K;Cimini M;Thandavarayan RA;Youker KA;Song X;Ren D;Li J;Kishore R;Krishnamurthy P;Wang L
糖尿病心肌病（DCM）的特征是微血管病变和间质纤维化，导致进行性心力衰竭。DCM发病机制尚不清楚，目前尚无有效的治疗方法。在本研究中，我们观察到STK 35，一种新的激酶，在糖尿病人类心脏中减少。模拟糖尿病高血糖的高糖治疗下调了小鼠心脏内皮细胞（MCEC）中STK 35的表达。STK 35的敲除减弱了MCEC的增殖、迁移和管形成，而STK 35的过表达恢复了高糖抑制的MCEC迁移和管形成。血管生成基因PCR阵列分析显示，HG下调了几个血管生成基因的表达，STK 35过表达完全恢复了这种抑制。静脉内注射AAV 9-STK 35病毒颗粒成功地在糖尿病小鼠心脏中过表达STK 35，导致血管密度增加，心脏纤维化抑制和左心室功能改善。总之，我们的研究结果表明，高血糖下调内皮STK 35的表达，导致糖尿病心脏微血管功能障碍，代表了DCM发病机制的一种新机制。STK 35是一个新的防治DCM的基因治疗靶点。
Diabetic cardiomyopathy (DCM) is characterized by microvascular pathology and interstitial fibrosis that leads to progressive heart failure. The mechanisms underlying DCM pathogenesis remain obscure, and no effective treatments for the disease have been available. In the present study, we observed that STK35, a novel kinase, is decreased in the diabetic human heart. High glucose treatment, mimicking hyperglycemia in diabetes, downregulated STK35 expression in mouse cardiac endothelial cells (MCEC). Knockdown of STK35 attenuated MCEC proliferation, migration, and tube formation, whereas STK35 overexpression restored the high glucose-suppressed MCEC migration and tube formation. Angiogenesis gene PCR array analysis revealed that HG downregulated the expression of several angiogenic genes, and this suppression was fully restored by STK35 overexpression. Intravenous injection of AAV9-STK35 viral particles successfully overexpressed STK35 in diabetic mouse hearts, leading to increased vascular density, suppression of fibrosis in the heart, and amelioration of left ventricular function. Altogether, our results suggest that hyperglycemia downregulates endothelial STK35 expression, leading to microvascular dysfunction in diabetic hearts, representing a novel mechanism underlying DCM pathogenesis. Our study also emerges STK35 is a novel gene therapeutic target for preventing and treating DCM.
影响因子：
5
作者：
Fischer KM;Cottage CT;Konstandin MH;Völkers M;Khan M;Sussman MA
通讯作者：
Sussman MA