title: Induction of autophagy markers is associated with attenuation of miR-133a in diabetic heart failure patients undergoing mechanical unloading.
abstract: Autophagy is ubiquitous in all forms of heart failure and cardioprotective miR-133a is attenuated in human heart failure. Previous reports from heart failure patients undergoing left ventricular assist device (LVAD) implantation demonstrated that autophagy is upregulated in the LV of the failing human heart. Studies in the murine model show that diabetes downregulates miR-133a. However, the role of miR-133a in the regulation of autophagy in diabetic hearts is unclear. We tested the hypothesis that diabetes exacerbates cardiac autophagy by inhibiting miR-133a in heart failure patients undergoing LVAD implantation. The miRNA assay was performed on the LV of 15 diabetic (D) and 6 non-diabetic (ND) heart failure patients undergoing LVAD implantation. Four ND with highly upregulated and 5 D with highly downregulated miR-133a were analyzed for autophagy markers (Beclin1, LC3B, ATG3) and their upstream regulators (mTOR and AMPK), and hypertrophy marker (beta-myosin heavy chain) by RT-qPCR, Western blotting and immunofluorescence. Our results demonstrate that attenuation of miR-133a in diabetic hearts is associated with the induction of autophagy and hypertrophy, and suppression of mTOR without appreciable difference in AMPK activity. In conclusion, attenuation of miR-133a contributes to the exacerbation of diabetes mediated cardiac autophagy and hypertrophy in heart failure patients undergoing LVAD implantation.
authors.affiliation: Department of Cellular, Integrative Physiology, University of Nebraska Medical Center Omaha, NE 68198, USA.
authors.forename: Shyam Sundar
authors.initials: SS
authors.lastname: Nandi
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Nebraska Medical Center Omaha, NE 68198, USA ; Veterans Affair Nebraska-Western Iowa Health Care System, Research Services 151 4101 Woolworth Avenue, Omaha NE 68105, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Duryee
authors.affiliation: Department of Cellular, Integrative Physiology, University of Nebraska Medical Center Omaha, NE 68198, USA.
authors.forename: Hamid R
authors.initials: HR
authors.lastname: Shahshahan
authors.affiliation: Department of Medicine, Division of Rheumatology, University of Nebraska Medical Center Omaha, NE 68198, USA ; Veterans Affair Nebraska-Western Iowa Health Care System, Research Services 151 4101 Woolworth Avenue, Omaha NE 68105, USA.
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Thiele
authors.affiliation: Department of Medicine, Division of Cardiology, University of Nebraska Medical center Omaha, NE 68198, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Anderson
authors.affiliation: Department of Cellular, Integrative Physiology, University of Nebraska Medical Center Omaha, NE 68198, USA ; Department of Anesthesiology, University of Nebraska Medical Center Omaha, NE 68198, USA.
authors.forename: Paras K
authors.initials: PK
authors.lastname: Mishra
keywords: AMPK; Beclin1; Hypertrophy; LC3B; LVAD; Milrinone; mTOR