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CPT1a Expression Is a Critical Cardioprotective Response to Pathological Stress That Enables Rescue by Gene Transfer
Andrew N Carley1,2, Santosh K Maurya1,2, Chandan K Maurya1,2
1Department of Internal Medicine (A.N.C., S.K.M., C.K.M., Y.W., A.A.C., E.D.L.), The Ohio State University College of Medicine, Columbus.
Insights
Carnitine palmitoyl transferase 1a (CPT1a) upregulation protects the heart during stress by suppressing harmful gene programs. This adaptation is crucial in nonischemic cardiomyopathy, mitigating adverse remodeling and improving cardiac function.
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.
Background:
CPT1 (carnitine palmitoyltransferase 1) is a rate-limiting enzyme for long-chain fatty acid oxidation. In adult hearts, CPT1b predominates, while CPT1a is coexpressed at lower levels. Pathological stress on the heart induces CPT1a expression, coinciding with a reduction in fatty acid oxidation, yet the role of CPT1a in pathological remodeling is unknown.
Methods:
CPT1 isoform expression was assayed in the myocardium of patients with heart failure with nonischemic cardiomyopathy and a preclinical mouse model of heart failure. Mice were subjected to afterload stress via transverse aortic constriction (TAC) or sham surgery (sham) with cardiac-specific CPT1a knockdown or cardiac-specific, adeno-associated virus serotype 9 (AAV9)-mediated CPT1a overexpression (AAV9.cTnT [cardiac troponin T].Cpt1a) versus empty virus or PBS infusions as controls. MicroRNA 370, known to suppress hepatic CPT1a, was assayed and overexpressed to determine if microRNA 370 regulates cardiac CPT1a expression.
Results:
CPT1a protein was elevated and microRNA 370 reduced in the myocardium of male and female patients with nonischemic cardiomyopathy, as well as in failing mouse hearts. AAV9-mediated microRNA 370 overexpression in mouse hearts suppressed CPT1a expression and attenuated the response of CPT1a to TAC. Preventing CPT1a upregulation in response to TAC in cardiac-specific CPT1a knockout mice exacerbated adverse remodeling, severe dysfunction, and increased mortality. In contrast, CPT1a overexpression (2.8-fold) attenuated impaired ejection fraction (by 54%) versus control TAC hearts (P<0.05). Delivery of AAV9.cTnT.Cpt1a 4 weeks after TAC surgery led to significant rescue of ejection fraction and mitigated the exacerbated dysfunction of cardiac-specific CPT1a knockout mice TAC hearts. RNA-seq revealed a novel function of CPT1a in suppressing hypertrophic, profibrotic, and cell death gene programs in both sham and TAC hearts, irrespective of changes in fatty acid oxidation, with reduced histone acetylation.
Conclusions:
The effects of CPT1a in the heart extend beyond fatty acid oxidation including noncanonical regulation of gene programs. CPT1a upregulation occurs in nonischemic cardiomyopathy and is a critical cardioprotective adaptation to pathological stress.
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