Augmenting Vacuolar H⁺-ATPase Function Prevents Cardiomyocytes from Lipid-Overload Induced Dysfunction

Area of Science:

• Cardiology
• Metabolic Research
• Cell Biology

Background:

• Diabetic cardiomyopathy involves a shift from glucose to lipid metabolism in the heart.
• This shift increases lipid transporter CD36 (SR-B2) at the sarcolemma, leading to lipid accumulation and contractile dysfunction.
• Vacuolar H+-ATPase (v-ATPase) activity is crucial for retaining CD36 within endosomes.

Purpose of the Study:

• To investigate if enhancing glucose availability can restore normal substrate utilization and contractile function in lipid-overloaded cardiomyocytes.
• To determine the role of vacuolar H+-ATPase (v-ATPase) in mediating the effects of glucose on cardiomyocyte metabolism and function.

Main Methods:

• HL-1 cardiomyocytes, adult rat, and human cardiomyocytes were cultured under high-lipid conditions.
• Increased glucose availability was induced by high glucose (25 mM) or adenoviral overexpression of protein kinase-D1.
• Evaluated v-ATPase re-assembly, endosomal acidification, CD36 localization, lipid accumulation, insulin-stimulated GLUT4 translocation, glucose uptake, and contractile force.

Main Results:

• Both high glucose and protein kinase-D1 overexpression stimulated v-ATPase re-assembly and endosomal acidification.
• These treatments led to endosomal CD36 retention and prevented myocellular lipid accumulation.
• Preserved insulin-stimulated GLUT4 translocation, glucose uptake, and contractile force in treated cardiomyocytes.

Conclusions:

• Vacuolar H+-ATPase (v-ATPase) acts as a critical regulator of cardiomyocyte substrate preference.
• Manipulating glucose availability via v-ATPase offers a potential therapeutic strategy for diabetic heart conditions.
• Restoring glucose metabolism can reverse lipid-induced contractile dysfunction in cardiomyocytes.