Potential role of the mTOR-C1-PGC1α-PPARα axis under type-II diabetes and hypertension in the human heart

Abstract Background: Type-2 diabetes (T2DM) and arterial hypertension (HTN) are major risk factors for heart failure. Importantly, these pathologies could induce synergetic alterations in the heart, and the discovery of key molecular signaling may suggest new targets for therapy. Methods and Results:: Intraoperative cardiac biopsies were obtained from patients with or without HTN and/or T2DM. Control (n=5), HTN (n=7) and HTN+T2DM (n=7) samples were analyzed by proteomics and bioinformatics. Cultured cardiomyocytes were used for further in vitro studies. In cardiac biopsies from patients with cardiopathy but preserved systolic function we found significant alterations of 677 proteins. After filtered out non-cardiac factors, 529 and 41 were changed in HTN-T2DM and in HTN subjects, respectively, against control. Interestingly, 81% of proteins in HTN-T2DM were distinct from HTN, while 95% from HTN were common with HTN-T2DM. In addition, 78 factors were differentially expressed in HTN-T2DM against HTN, predominantly downregulated proteins of mitochondrial respiration and lipid oxidation. Bioinformatic analyses suggested implication of mTOR signaling and reduction of AMPK and PPARα activation, and regulation of PGC1α, fatty acid oxidation, and oxidative phosphorylation. In cultured cardiomyocytes, an excess of palmitate activated mTOR-C1 complex and subsequent attenuation of PGC1α-PPARα transcription of b-oxidation and mitochondrial electron chain factors, affecting the mitochondrial/glycolytic ATP synthesis. Conclusions: The coexistence of HTN and T2DM induced higher alterations in cardiac proteins than HTN. HTN-T2DM subjects exhibited a dramatic downregulation of mitochondrial respiration and lipid metabolism. The mTOR-C1-PGC1α-PPARα axis might account as a target for future therapies.