Tuberous sclerosis complex 2 deficiency in cardiomyocytes exacerbates cardiac remodeling in diabetic mice.

BACKGROUNDBased on gene expression profiles from the BioGPS database, Tuberous sclerosis complex 2 (Tsc2) exhibited the highest expression in mouse cardiac tissues. Herein, we investigated the potential functional role of Tsc2 in diabetic cardiomyopathy.

METHODS AND RESULTSCardiac-specific Tsc2 deletion exacerbated myocardial fibrosis and cardiac dysfunction in streptozotocin-induced diabetic mice. Whole-transcriptomic analysis combined with single cell-sequencing analysis from the Human Protein Atlas database demonstrated that Tsc2 deletion enhanced Angiopoietin-like protein 7 (Angptl7) expression in cardiomyocytes under hyperglycemia. Recombinant adeno-associated virus serotype 9 carrying Angptl7 shRNA under cardiac troponin T promoter substantially reversed Tsc2 deletion-induced cardiac remodeling and dysfunction in diabetic mice. Mechanistically, the study demonstrated that cardiomyocyte-released Angptl7 activated β-Catenin in fibroblasts and promoted cardiac fibrosis through a paracrine mechanism. Furthermore, chronic supplementation with leucine, an essential branched-chain amino acid, led to adverse cardiac remodeling and dysfunction through Angptl7 activation in diabetic mice.

CONCLUSIONSOur findings demonstrate that Tsc2 deficiency in cardiomyocytes disrupts cardiac homeostasis and contributes to the progression of diabetic cardiomyopathy. The results also suggest that targeting Angptl7 represents a potential therapeutic strategy for diabetic cardiomyopathy, particularly in patients with Tsc2 mutation.