ADAM17 knockdown is more effective than AT1R blocker in alleviating diabetic cardiomyopathy through downregulating...

Area of Science:

• Cardiovascular Research
• Diabetology
• Molecular Medicine

Background:

• Diabetic cardiomyopathy (DCM) significantly increases mortality in diabetic patients.
• The precise mechanisms of ADAM17 (a disintegrin and metalloproteinase 17) in preventing cardiac fibrosis are not fully understood.
• ADAM17 is a novel component of the renin-angiotensin-aldosterone system (RAAS).

Purpose of the Study:

• To investigate the role of ADAM17 in DCM pathogenesis.
• To elucidate the interaction between ADAM17 and the RhoA/ROCK1 signaling pathway.
• To evaluate ADAM17's impact on cardiac fibroblast-to-myofibroblast transition and cardiac remodeling.

Main Methods:

• Adeno-associated virus 9 (AAV9)-mediated gene silencing of ADAM17 in diabetic mice.
• Assessment of cardiac function and fibrosis.
• Comparison with losartan, an angiotensin II type 1 receptor (AT1R) antagonist.
• Analysis of RhoA/ROCK1 signaling pathway activation and myofibroblast differentiation.

Main Results:

• ADAM17 silencing significantly decreased collagen deposition and pro-fibrotic markers.
• Both ADAM17 knockdown and losartan treatment attenuated RhoA/ROCK1 pathway activation.
• High glucose-induced myofibroblast differentiation was inhibited by both treatments.
• ADAM17 knockdown demonstrated superior efficacy over losartan in improving cardiac function and reducing fibrosis.

Conclusions:

• Targeting ADAM17 and the RhoA/ROCK1 pathway presents a potential therapeutic strategy for DCM.
• ADAM17 plays a crucial role in the molecular mechanisms underlying DCM.
• Intervention targeting ADAM17 may offer improved outcomes for diabetic cardiomyopathy patients.