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oai:repisalud.isciii.es:20.500.12105/71382024-10-31T11:55:36Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Caravia, Xurde M author Fanjul, Victor author Oliver, Eduardo author Roiz-Valle, David author Morán-Álvarez, Alba author Desdín-Micó, Gabriela author Mittelbrunn, María author Cabo, Roberto author Vega, José A author Rodríguez, Francisco author Fueyo, Antonio author Gomez, Monica author Lobo-Gonzalez, Manuel author Bueno, Hector author Velasco, Gloria author Freije, José M P author Andres, Vicente author Ibáñez, Borja author Ugalde, Alejandro P author López-Otín, Carlos author 2018-10 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. PLoS Biol. 2018; 16(10):e2006247 1545-7885 http://hdl.handle.net/20.500.12105/7138 30346946 10.1371/journal.pbio.2006247 1545-7885 PLoS biology The microRNA-29/PGC1α regulatory axis is critical for metabolic control of cardiac function