Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter.

Abstract

Comparative analyses of transcriptional profiles from humans and mice with cardiovascular pathologies revealed consistently elevated expression of <i>MICU2</i>, a regulatory subunit of the mitochondrial calcium uniporter complex. To determine if <i>MICU2</i> expression was cardioprotective, we produced and characterized <i>Micu2</i>^<i>-/-</i> mice. Mutant mice had left atrial enlargement and <i>Micu2</i>^<i>-/-</i> cardiomyocytes had delayed sarcomere relaxation and cytosolic calcium reuptake kinetics, indicating diastolic dysfunction. RNA sequencing (RNA-seq) of <i>Micu2</i>^<i>-/-</i> ventricular tissues revealed markedly reduced transcripts encoding the apelin receptor (<i>Micu2</i>^<i>-/-</i> vs. wild type, <i>P</i> = 7.8 × 10^-40), which suppresses angiotensin II receptor signaling via allosteric transinhibition. We found that <i>Micu2</i>^<i>-/-</i> and wild-type mice had comparable basal blood pressures and elevated responses to angiotensin II infusion, but that <i>Micu2</i>^<i>-/-</i> mice exhibited systolic dysfunction and 30% lethality from abdominal aortic rupture. Aneurysms and rupture did not occur with norepinephrine-induced hypertension. Aortic tissue from <i>Micu2</i>^<i>-/-</i> mice had increased expression of extracellular matrix remodeling genes, while single-cell RNA-seq analyses showed increased expression of genes related to reactive oxygen species, inflammation, and proliferation in fibroblast and smooth muscle cells. We concluded that <i>Micu2</i>^<i>-/-</i> mice recapitulate features of diastolic heart disease and define previously unappreciated roles for <i>Micu2</i> in regulating angiotensin II-mediated hypertensive responses that are critical in protecting the abdominal aorta from injury.