Activation of the mTORC1 and mitochondrial signaling under diabetic and hypertensive cardiomyopathy
Authors:   IIS-Fundación Jiménez Díaz, UAM, Hang T , Corrales S ,   IIS-Fundación Jiménez Díaz, UAM, Azkargorta M ,   Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Lumpuy-Castillo J ,   IIS-Fundación Jiménez Díaz, UAM, Elortza F ,   Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Martínez-Chantar M ,   Liver Disease Laboratory, Center for Cooperative Research in Biosciences (CIC bioGUNE), Basque Research and Technology Alliance (BRTA), Bizkaia Technology Park, Building 801A, 48160 Derio, Spain. Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Lorenzo O ,   IIS-Fundación Jiménez Díaz, UAM
Published: June 2022

Introduction: Type 2 Diabetes Mellitus (T2DM) and hypertension (HTN) are correlated with cardiovascular disease (CVD). The presence of HTN in T2DM will lead to risk elevation in CVD. Inflammation, hypertrophy, apoptosis and fibrosis can be found in these patients. However, the mechanisms involved haven’t been fully depicted. Methodology: Cardiac biopsies from interventricular septum were isolated from patients with T2DM and/or HTN. Differential protein expression was evaluated by proteomics (hybrid trapped ion mobility spectrometry) and PEAKS software. Ingenuity Pathway Analysis (IPA, Qiagen) was used to predict the implication of molecular pathways. Cultured cardiomyocytes were used to reveal the alteration of relevant pathways under hyperglycemic, hyperlipidemic and pro-hypertensive milieu mimicked by high glucose, high fatty-acid (HF) and/or angiotensin-II. Results: By proteomics, there is a huge difference between T2DM/HTN group and HTN in number of altered factors and its fold-change when compared with control. HTN induced a decrease of cardiac factors related to carbohydrate metabolism, mitochondrial homeostasis and respiration, while factors decreased in T2DM/HTN most related to metabolism and mitochondrial dysfunction. Also, T2DM/HTN increased fibrosis and apoptosis related factors. Interestingly, a potential regulation of mTOR complexes was suggested by bioinformatics. Thus, we confirmed the phosphorylation on Thr421/Ser424 of p70S6, a mTORC1 downstream mediator, under HF in cardiomyocytes. Also, we observed an enhanced phosphorylation on Thr172 of AMPKα, and a decreased expression of PGC1α and ACADm, in parallel to a lessening of ATP production. These alterations were abolished by rapamycin, an inhibitor of mTORC1 and metformin. Also, the silencing of a subunit of mTORC2, Rictor, induced a decrease of p-p70s6 under HF. Conclusion: T2DM/ HTN can lead to dramatic protein changes in heart and induce a synergy cooperation when combined. The mitochondrial alteration may be major responsible of cardiac dysfunction. In particular, mTORC1 can be activated under hyperlipidemia to further lead to β-oxidation reduction and ATP synthesis. Therefore, the regulation of the mTOR-mitochondria signaling could be essential for prognosis of heart failure in T2DM and HTN patients.