Bick, AlexanderWakimoto, HirokoKamer, KimberliSancak, YaseminGoldberger, OlgaAxelsson, AnnaDeLaughter, DanielGorham, JoshuaMootha, VamsiSeidman, J. G.Seidman, Christine2017-12-062017Bick, A. G., H. Wakimoto, K. J. Kamer, Y. Sancak, O. Goldberger, A. Axelsson, D. M. DeLaughter, et al. 2017. “Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter.” Proceedings of the National Academy of Sciences of the United States of America 114 (43): E9096-E9104. doi:10.1073/pnas.1711303114. http://dx.doi.org/10.1073/pnas.1711303114.http://nrs.harvard.edu/urn-3:HUL.InstRepos:34493306Comparative 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.en-USMedical Sciencesmitochondrial calcium uniporterdiastolic dysfunctionaortic aneurysmshypertensioncalciumJournal Article2017-12-0610.1073/pnas.1711303114