Potential Role of the mTORC1-PGC1α-PPARα Axis under Type-II Diabetes and Hypertension in the Human Heart

Abstract

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 common molecular signaling may suggest new targets for therapy. Intraoperative cardiac biopsies were obtained from patients with coronary heart disease and preserved systolic function, with or without HTN and/or T2DM, who underwent coronary artery bypass grafting (CABG). Control (n = 5), HTN (n = 7), and HTN + T2DM (n = 7) samples were analysed by proteomics and bioinformatics. Additionally, cultured rat cardiomyocytes were used for the analysis (protein level and activation, mRNA expression, and bioenergetic performance) of key molecular mediators under stimulation of main components of HTN and T2DM (high glucose and/or fatty acids and angiotensin-II). As results, in cardiac biopsies, we found significant alterations of 677 proteins and after filtering for non-cardiac factors, 529 and 41 were changed in HTN-T2DM and in HTN subjects, respectively, against the 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 the 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 the palmitate activated mTORC1 complex and subsequent attenuation of PGC1α-PPARα transcription of β-oxidation and mitochondrial electron chain factors affect mitochondrial/glycolytic ATP synthesis. Silencing of PGC1α further reduced total ATP and both mitochondrial and glycolytic ATP. Thus, the coexistence of HTN and T2DM induced higher alterations in cardiac proteins than HTN. HTN-T2DM subjects exhibited a marked downregulation of mitochondrial respiration and lipid metabolism and the mTORC1-PGC1α-PPARα axis might account as a target for therapeutical strategies.

Implications of Activating the ANT2/mTOR/PGC-1α Feedback Loop: Insights into Mitochondria-Mediated Injury in Hypoxic Myocardial Cells

“…Furthermore, we found that the inhibition of ANT2 can upregulate mTOR levels, subsequently blocking the expression of PGC-1α, a critical factor for mitochondrial metabolism and biogenesis. Recently, Hang et al also reported that PGC-1α can be inhibited by the activation of mTORC1, deteriorating the mitochondrial functions [31]. It is important to note that PGC-1α, which is activated by mTOR, can also enhance the transcription of ANT2 [32].…”

Qiliqiangxin: A multifaceted holistic treatment for heart failure or a pharmacological probe for the identification of cardioprotective mechanisms?

“…The cardiac expression of PGC-1α, PPARα and downstream effectors is downregulated, but the expression of PPARγ is upregulated, in patients with hypertensive, coronary artery disease or heart failure. [73][74][75][76][77] The PPARα agonist fenofibrate restores PPARα signalling and reduced heart failure events in a large-scale clinical trial. 78 Conversely, both selective PPARγ and dual PPARα/PPARγ agonists have been shown to increase the risk of heart failure events in clinical trials, [23][24][25] and long-term activation of NRF2 (the downstream effector of PPARγ 76 ) with bardoxolone increased the risk of death or hospitalization for heart failure in a large-scale trial.…”

“…The balance of PPARα/PPARγ signalling has important implications for patients with cardiomyopathy ( Figure ). The cardiac expression of PGC‐1α, PPARα and downstream effectors is downregulated, but the expression of PPARγ is upregulated, in patients with hypertensive, coronary artery disease or heart failure 73–77 . The PPARα agonist fenofibrate restores PPARα signalling and reduced heart failure events in a large‐scale clinical trial 78 .…”