Abstract
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.
Highlights
Diabetes mellitus is a metabolic disease characterized by high blood glucose levels [1,2,3]
To explore if serine-threonine kinase 35 (STK35) is dysregulated in diabetes and contributes to diabetic cardiomyopathy (DCM), we initially analyzed publicly available mRNA expression data from 7 human diabetic hearts and 5 human non-diabetic heart controls (GSE26887)
We found a significant decrease in STK35 mRNA expression in human diabetic hearts compared to human non-diabetic hearts (Figure 1A)
Summary
Diabetes mellitus is a metabolic disease characterized by high blood glucose levels [1,2,3]. Untreated high blood sugar in diabetes damages organs and tissues throughout the patient‘s body leading to complications such as cardiovascular disease. Often presenting as cardiomyopathy, is the leading cause of death among patients with diabetes mellitus [4,5,6]. Despite the recent advances in understanding diabetic cardiomyopathy (DCM), the full spectrum of contributing mechanisms. STK35 Improves Cardiac Functions in Diabetes and their relative contribution to DCM remains obscure. No approved effective treatments for diabetes-induced cardiac dysfunction exists. Identifying novel mechanisms underlying DCM development and specific therapies targeting diabetes-induced cardiac dysfunction and subsequent heart failure are urgently needed [7]
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