CPT1a Expression Is a Critical Cardioprotective Response to Pathological Stress That Enables Rescue by Gene Transfer.
Level 5 - mechanism / opinion, no new human data
Preclinical animal intervention and observational human tissue analysis
PubMed 41342119 · doi:10.1161/CIRCRESAHA.125.327403
What was done
Researchers evaluated CPT1a expression and microRNA 370 regulation in myocardial tissue from male and female patients with nonischemic cardiomyopathy and mouse models of heart failure. Mice underwent transverse aortic constriction (TAC) or sham surgery combined with cardiac-specific CPT1a knockout, microRNA 370 overexpression, or AAV9-mediated cardiac-specific CPT1a overexpression (AAV9.cTnT.Cpt1a) compared to empty virus or PBS controls. Therapeutic gene delivery was tested 4 weeks after TAC. RNA sequencing and histone acetylation assays were performed to evaluate downstream transcriptional effects.
What was found
CPT1a protein was elevated and microRNA 370 was reduced in failing human and mouse myocardium. Overexpression of microRNA 370 in mice suppressed CPT1a and blunted its response to TAC. Genetic deletion of CPT1a in TAC mice worsened adverse remodeling, cardiac dysfunction, and mortality. Conversely, 2.8-fold CPT1a overexpression reduced the impairment of ejection fraction by 54% compared to control TAC hearts (P < 0.05) and rescued ejection fraction when administered 4 weeks post-TAC. RNA sequencing showed CPT1a suppressed hypertrophic, profibrotic, and cell death pathways alongside reduced histone acetylation, independent of changes in fatty acid oxidation.
Why it matters
This study identifies CPT1a induction as an essential cardioprotective response in heart failure that works through noncanonical epigenetic and transcriptional repression. It establishes CPT1a gene transfer as a potential therapeutic strategy for pathological cardiac remodeling.
Limits
Findings are primarily derived from a mouse pressure-overload model (TAC), which may not fully capture the complexity of human nonischemic cardiomyopathy. The abstract does not provide sample sizes (n) for human myocardial samples or mouse cohorts, nor does it report baseline ejection fraction values or exact mortality rates.
Cited by
- supports Carnitine palmitoyltransferase (CPT) is the rate-limiting enzyme for transporting fatty acids into the mitochondria for beta-oxidation.