STK35 Gene Therapy Attenuates Endothelial Dysfunction and Improves Cardiac Function in Diabetes

Area of Science:

• Cardiovascular Biology
• Endocrinology
• Molecular Medicine

Background:

• Diabetic cardiomyopathy (DCM) is a serious complication of diabetes mellitus, characterized by progressive heart failure.
• The underlying mechanisms of DCM, including microvascular dysfunction and fibrosis, are not fully understood, and effective treatments are lacking.

Purpose of the Study:

• To investigate the role of STK35 kinase in the pathogenesis of diabetic cardiomyopathy.
• To explore STK35 as a potential therapeutic target for DCM.

Main Methods:

• Assessed STK35 expression in human diabetic hearts and high glucose-treated mouse cardiac endothelial cells (MCEC).
• Utilized STK35 knockdown and overexpression in MCEC to evaluate effects on cell function and angiogenesis.
• Administered AAV9-STK35 to diabetic mice to assess in vivo therapeutic potential.

Main Results:

• STK35 expression was decreased in diabetic human hearts and downregulated by high glucose in MCEC.
• STK35 knockdown impaired MCEC proliferation, migration, and tube formation; overexpression rescued high glucose-induced deficits.
• In vivo STK35 overexpression in diabetic mice increased vascular density, reduced cardiac fibrosis, and improved left ventricular function.

Conclusions:

• Hyperglycemia downregulates endothelial STK35, contributing to microvascular dysfunction and DCM pathogenesis.
• STK35 represents a novel therapeutic target for the prevention and treatment of diabetic cardiomyopathy.