CPT1a Expression Is a Critical Cardioprotective Response to Pathological Stress That Enables Rescue by Gene Transfer

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Carnitine palmitoyl transferase 1 (CPT1) is key in fatty acid oxidation, with CPT1b dominant in adult hearts and CPT1a coexpressed.
• Pathological heart stress increases CPT1a, yet its role in cardiac remodeling remains unclear.

Purpose of the Study:

• Investigate the role of CPT1a in pathological cardiac remodeling.
• Determine if microRNA 370 regulates cardiac CPT1a expression.

Main Methods:

• Assayed CPT1 isoform expression in human heart failure and a mouse model.
• Utilized cardiac-specific CPT1a knockdown and overexpression via AAV9.
• Examined microRNA 370's role in regulating CPT1a.

Main Results:

• CPT1a and reduced microRNA 370 were found in failing human and mouse hearts.
• MicroRNA 370 overexpression suppressed CPT1a and attenuated TAC response.
• CPT1a deficiency worsened TAC-induced heart failure, while CPT1a overexpression improved ejection fraction and mitigated dysfunction.

Conclusions:

• CPT1a's cardiac role transcends fatty acid oxidation, involving noncanonical gene program regulation.
• CPT1a upregulation is a cardioprotective adaptation in nonischemic cardiomyopathy and pathological stress.