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

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