title: Regulation of cardiac expression of the diabetic marker microRNA miR-29.
abstract: Diabetes mellitus (DM) is an independent risk factor for heart disease and its underlying mechanisms are unclear. Increased expression of diabetic marker miR-29 family miRNAs (miR-29a, b and c) that suppress the pro-survival protein Myeloid Cell Leukemia 1(MCL-1) is reported in pancreatic β-cells in Type 1 DM. Whether an up-regulation of miR-29 family miRNAs and suppression of MCL-1 (dysregulation of miR-29-MCL-1 axis) occurs in diabetic heart is not known. This study tested the hypothesis that insulin regulates cardiac miR-29-MCL-1 axis and its dysregulation correlates with DM progression. In vitro studies with mouse cardiomyocyte HL-1 cells showed that insulin suppressed the expression of miR-29a, b and c and increased MCL-1 mRNA. Conversely, Rapamycin (Rap), a drug implicated in the new onset DM, increased the expression of miR-29a, b and c and suppressed MCL-1 and this effect was reversed by transfection with miR-29 inhibitors. Rap inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling in HL-1 cells. Moreover, inhibition of either mTORC1 substrate S6K1 by PF-4708671, or eIF4E-induced translation by 4E1RCat suppressed MCL-1. We used Zucker diabetic fatty (ZDF) rat, a rodent model for DM, to test whether dysregulation of cardiac miR-29-MCL-1 axis correlates with DM progression. 11-week old ZDF rats exhibited significantly increased body weight, plasma glucose, insulin, cholesterol, triglycerides, body fat, heart weight, and decreased lean muscle mass compared to age-matched lean rats. Rap treatment (1.2 mg/kg/day, from 9-weeks to 15-weeks) significantly reduced plasma insulin, body weight and heart weight, and severely dysregulated cardiac miR-29-MCL1 axis in ZDF rats. Importantly, dysregulation of cardiac miR-29-MCL-1 axis in ZDF rat heart correlated with cardiac structural damage (disorganization or loss of myofibril bundles). We conclude that insulin and mTORC1 regulate cardiac miR-29-MCL-1 axis and its dysregulation caused by reduced insulin and mTORC1 inhibition increases the vulnerability of a diabetic heart to structural damage.
authors: Department of Medicine, University of Missouri, Columbia, Missouri, United States of America; Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, United States of America.
authors: Nicholas
authors: N
authors: Arnold
authors: Department of Medicine, University of Missouri, Columbia, Missouri, United States of America; Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, United States of America.
authors: Purushotham Reddy
authors: PR
authors: Koppula
authors: Department of Medicine, University of Missouri, Columbia, Missouri, United States of America; Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, United States of America; Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors: Rukhsana
authors: R
authors: Gul
authors: Department of Medicine, University of Missouri, Columbia, Missouri, United States of America; Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, United States of America.
authors: Christian
authors: C
authors: Luck
authors: Department of Medicine, University of Missouri, Columbia, Missouri, United States of America; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri, United States of America; Harry S Truman Memorial Veterans Affairs Hospital, Columbia, Missouri, United States of America.
authors: Lakshmi
authors: L
authors: Pulakat
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D048909:Diabetes Complications / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006331:Heart Diseases / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000097:blood; D050417:Insulin-Secreting Cells / Q000378:metabolism / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000096:biosynthesis* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D007328:Insulin; C579095:MCL1 protein, human; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D046912:Multiprotein Complexes; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus