CPT1a Expression Is a Critical Cardioprotective Response to Pathological Stress That Enables Rescue by Gene Transfer
Year: 2025
Type: article
Abstract: 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.
Source: Circulation Research
Authors: Andrew N. Carley, Santosh K. Maurya, Chandan K. Maurya, Yang Wang, Amy Webb, Azariyas A. Challa, Tatiana Gromova, Thomas M. Vondriska, Zhentao Zhang, Hua Zhu, Ahlke Heydemann, Kenneth C. Bedi, Christos P. Kyriakopoulos, Craig H. Selzman, Stavros G. Drakos, Kenneth B. Margulies, E. Douglas Lewandowski
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Clinical and Metabolic Signature of Recovered Myocardium in Human Heart Failure, Perm1 is a Novel Regulator of Cardiac Energetics and Function, Adipose tissue mediates cardiac metabolic remodeling in the pathologically stressed heart in the absence of primary metabolic stress, Functional, metabolic, and patient-centered determinants of recovery in heart failure, Inhibiting Cell Death for Protecting Cardiac Injury, Postdoctoral Training in Cardiometabolic Science, Maladaptive Expression of Metabolic Enzymes and Activity in Heart Failure, G9000266250, Cancer Center Support Grant, Dynamics of cardiac nuclei in heart disease, Training in Cardiovascular Research, Transendothelial transport and CD36 in the dysregulated lipid trafficking of failing hearts
OpenAlex ID: W4416984264