| First Author | Bick AG | Year | 2017 |
| Journal | Proc Natl Acad Sci U S A | Volume | 114 |
| Issue | 43 | Pages | E9096-E9104 |
| PubMed ID | 29073106 | Mgi Jnum | J:249367 |
| Mgi Id | MGI:6095209 | Doi | 10.1073/pnas.1711303114 |
| Citation | Bick AG, et al. (2017) Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter. Proc Natl Acad Sci U S A 114(43):E9096-E9104 |
| abstractText | 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 x 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. |
