MicroRNA Dysregulation in Diabetic Ischemic Heart Failure Patients
- Simona Greco1,
- Pasquale Fasanaro2,
- Serenella Castelvecchio3,
- Yuri D’Alessandra4,
- Diego Arcelli5,
- Marisa Di Donato6,
- Alexis Malavazos7,
- Maurizio C. Capogrossi2,
- Lorenzo Menicanti3 and
- Fabio Martelli2⇓
- 1Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Milan, Italy
- 2Vascular Pathology Laboratory, Istituto Dermopatico dell’Immacolata IRCCS, Rome, Italy
- 3Department of Cardiac Surgery, IRCCS Policlinico San Donato, Milan, Italy
- 4Vascular Biology and Regenerative Medicine Laboratory, Centro Cardiologico Monzino IRCCS, Milan, Italy
- 5Molecular Oncology Laboratory, Istituto Dermopatico dell’Immacolata IRCCS, Rome, Italy
- 6Department of Medical and Surgical Critical Care, Cardiology Section, University of Florence, Florence, Italy
- 7Diabetology and Metabolic Disease Unit, IRCCS Policlinico San Donato, Milan, Italy
- Corresponding author: Fabio Martelli, .
F.M. is currently affiliated with the Molecular Cardiology Laboratory, IRCCS Policlinico San Donato, Milan, Italy.
Increased morbidity and mortality associated with ischemic heart failure (HF) in type 2 diabetic patients requires a deeper understanding of the underpinning pathogenetic mechanisms. Given the implication of microRNAs (miRNAs) in HF, we investigated their regulation and potential role. miRNA expression profiles were measured in left ventricle biopsies from 10 diabetic HF (D-HF) and 19 nondiabetic HF (ND-HF) patients affected by non–end stage dilated ischemic cardiomyopathy. The HF groups were compared with each other and with 16 matched nondiabetic, non-HF control subjects. A total of 17 miRNAs were modulated in D-HF and/or ND-HF patients when compared with control subjects. miR-216a, strongly increased in both D-HF and ND-HF patients, negatively correlated with left ventricular ejection fraction. Six miRNAs were differently expressed when comparing D-HF and ND-HF patients: miR-34b, miR-34c, miR-199b, miR-210, miR-650, and miR-223. Bioinformatic analysis of their modulated targets showed the enrichment of cardiac dysfunctions and HF categories. Moreover, the hypoxia-inducible factor pathway was activated in the noninfarcted, vital myocardium of D-HF compared with ND-HF patients, indicating a dysregulation of the hypoxia response mechanisms. Accordingly, miR-199a, miR-199b, and miR-210 were modulated by hypoxia and high glucose in cardiomyocytes and endothelial cells cultured in vitro. In conclusion, these findings show a dysregulation of miRNAs in HF, shedding light on the specific disease mechanisms differentiating diabetic patients.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0952/-/DC1.
- Received July 11, 2011.
- Accepted January 26, 2012.
- © 2012 by the American Diabetes Association.
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