Suchergebnisse

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. ; ERC-Advanced Grant, DeAge - European Union (grant number 742067). Received by CL-O. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ministerio de Economı´a y Competitividad. Received by CL-O. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Instituto de Salud Carlos III. Received by CL-O. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Centro de Investigacion Biomedica en Red de Cancer CIBERONC. Received by CL-O. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Plan Feder. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Progeria Research Foundation. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Instituto Universitario de Oncologı´a is supported by Fundacio´n Bancaria Caja de Ahorros de Asturias. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The Centro Nacional de Investigaciones Cardiovasculares (CNIC) is supported by the Ministry of Economy, Industry and Competitiveness (MINECO), and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence. (grant number SEV-2015-0505). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. APU is supported by the Human Frontier Science Program. (grant numberLT000640/2013). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. EO is supported by the 'Talent Attraction program' of Comunidad de Madrid. (grant number 2017-T1/ BMD-5185). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. ; Sí