Differential expression of metabolic genes distinguishes physiological from pathological cardiac hypertrophy

Cardiac hypertrophy is an adaptive or maladaptive response to physiological or pathological stimuli, with distinct functional outcomes. Metabolic reprogramming plays a key role in this process; however, the metabolism-associated genes underlying different remodeling patterns remain unclear. Transcriptomic microarray data related to cardiac hypertrophy (GSE776) were obtained from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were identified by comparing physiological (exercise-induced) and pathological (high-salt diet-induced) hypertrophy models with controls. Metabolism-associated genes were retrieved from the Molecular Signatures Database (MSigDB) and intersected with physiological hypertrophy-specific DEGs to identify candidate metabolic genes. Protein-protein interaction (PPI) analysis was performed to identify hub genes. Experimental validation was performed using mouse models of pregnancy-induced physiological hypertrophy and isoproterenol-induced pathological hypertrophy, isoproterenol-treated neonatal rat cardiomyocytes, and human myocardial tissue samples. Transcriptomic analysis identified 48 genes specifically associated with physiological cardiac hypertrophy, which were predominantly enriched in metabolic pathways. Intersection of these genes with metabolism-related gene sets revealed 22 physiological hypertrophy-related metabolic genes. PPI analysis identified HADHA, ACOX1 and GOT2 as key hub genes. In vivo and in vitro experiments demonstrated that these genes were significantly upregulated in physiological cardiac hypertrophy but markedly downregulated in pathological hypertrophy. Immunohistochemical analysis of human myocardial tissues confirmed reduced expression of HADHA, ACOX1 and GOT2 in pathological hypertrophic myocardium compared with non-hypertrophic controls. Differential expression of HADHA, ACOX1, and GOT2 highlights altered fatty acid oxidation and mitochondrial energy metabolism as key features distinguishing physiological and pathological cardiac hypertrophy.