Regulation of cardiac expression of the diabetic marker microRNA miR-29

• Published in: PloS one 2014-07, Vol.9 (7), p.e103284
• Main Authors: Arnold, Nicholas, Koppula, Purushotham Reddy, Gul, Rukhsana, Luck, Christian, Pulakat, Lakshmi
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Alzheimers disease; Animals; Apoptosis; Biology and Life Sciences; Blood Glucose - drug effects; Body fat; Body weight; Cancer therapies; Cardiomyocytes; Cardiomyopathy; Cardiovascular disease; Cardiovascular diseases; Cell survival; Cholesterol; Coronary artery disease; Diabetes; Diabetes Complications - genetics; Diabetes Complications - pathology; Diabetes mellitus; Gene expression; Gene Expression Regulation - drug effects; Glucose; Health risks; Heart; Heart diseases; Heart Diseases - etiology; Heart Diseases - genetics; Heart Diseases - pathology; Heart failure; Hospitals; Humans; Hyperglycemia; Initiation factor eIF-4E; Insulin; Insulin - blood; Insulin resistance; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; Kinases; Leukemia; Mcl-1 protein; Mechanistic Target of Rapamycin Complex 1; Medicine; Medicine and Health Sciences; Mice; MicroRNA; MicroRNAs; MicroRNAs - biosynthesis; MicroRNAs - genetics; miRNA; Model testing; mRNA; Multiprotein Complexes - antagonists & inhibitors; Multiprotein Complexes - metabolism; Muscles; Myeloid Cell Leukemia Sequence 1 Protein - biosynthesis; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - pathology; Pancreas; Pancreatic beta cells; Rapamycin; Rats; Ribonucleic acid; Risk factors; RNA; Rodents; Signaling; Sirolimus - administration & dosage; Studies; Substrate inhibition; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism; Transfection; Triglycerides; Veterans; Weight reduction
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0103284

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.