Chamber-specific cardiac proteome remodeling in a Göttingen minipig model of obesity and diabetes

BACKGROUND: Obesity and Type 2 Diabetes are major contributors to cardiac hypertrophy and dysfunction, yet the molecular mechanisms driving early myocardial alterations remain incompletely understood. Evidence from rodent models and end-stage human disease suggests that cytoskeletal remodeling and oxidative stress may contribute to early increases in cardiomyocyte stiffness and hypertrophy. Whether these processes are involved at earlier disease stages in translationally relevant large-animal models remains unclear. METHODS: Heart tissue from male Göttingen minipigs subjected to a 13-month intervention with a standard control diet, high-fat-fructose-cholesterol diet, or high-fat-fructose-cholesterol with streptozotocin-induced diabetes was analyzed. Untargeted proteomics was performed on left atrium and left ventricle tissue, followed by pathway enrichment analyses to identify diet- and chamber-specific proteomic alterations. RESULTS: Global proteomic analyses revealed that anatomical region represented the dominant source of variance, with ~ 200-300 proteins significantly regulated across dietary interventions. Pathway enrichment analyses highlighted alterations in protein and macronutrient metabolism, mitochondrial function, and extracellular matrix organization. Correlation and Hallmark analyses further linked ventricular remodeling to glucose-associated and mitochondrial pathways, while atrial remodeling was more closely associated with metabolic and nutrient-sensing pathways. Among 75 microtubule and 53 redox-related proteins examined, 16 and 14, respectively, were significantly altered in a chamber- and intervention-dependent manner. CONCLUSION: Early cardiac hypertrophy associated with obesity and/or diabetes is accompanied by extensive proteomic remodeling, characterized by distinct atrial and ventricular profiles. However, the relatively modest changes in microtubule and redox-related proteins suggest that these are unlikely to be primary drivers of early myocardial remodeling.