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PLoS Biol. 2018 Oct 22;16(10):e2006247. doi: 10.1371/journal.pbio.2006247. eCollection 2018 Oct.

The microRNA-29/PGC1α regulatory axis is critical for metabolic control of cardiac function.

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Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Spain.
Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
Cardiology Department and Instituto de Investigación i+12, Hospital Universitario 12 de Octubre, Madrid, Spain.
Departamento de Morfología y Biología Celular, Facultad de Medicina, Universidad de Oviedo, Oviedo, Spain.
Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Chile.
Área de Fisiología, Departamento de Biología Funcional, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, Spain.
Complejo Hospitalario Ruber Juan Bravo, Madrid, Spain.
Facultad de Medicina, Universidad Complutense de Madrid, Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Spain.
IIS-Fundación Jiménez Díaz Hospital, Madrid, Spain.


Different microRNAs (miRNAs), including miR-29 family, may play a role in the development of heart failure (HF), but the underlying molecular mechanisms in HF pathogenesis remain unclear. We aimed at characterizing mice deficient in miR-29 in order to address the functional relevance of this family of miRNAs in the cardiovascular system and its contribution to heart disease. In this work, we show that mice deficient in miR-29a/b1 develop vascular remodeling and systemic hypertension, as well as HF with preserved ejection fraction (HFpEF) characterized by myocardial fibrosis, diastolic dysfunction, and pulmonary congestion, and die prematurely. We also found evidence that the absence of miR-29 triggers the up-regulation of its target, the master metabolic regulator PGC1α, which in turn generates profound alterations in mitochondrial biogenesis, leading to a pathological accumulation of small mitochondria in mutant animals that contribute to cardiac disease. Notably, we demonstrate that systemic hypertension and HFpEF caused by miR-29 deficiency can be rescued by PGC1α haploinsufficiency, which reduces cardiac mitochondrial accumulation and extends longevity of miR-29-mutant mice. In addition, PGC1α is overexpressed in hearts from patients with HF. Collectively, our findings demonstrate the in vivo role of miR-29 in cardiovascular homeostasis and unveil a novel miR-29/PGC1α regulatory circuitry of functional relevance for cell metabolism under normal and pathological conditions.

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Conflict of interest statement

The authors have declared that no competing interests exist.

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