Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter.
Cardiovascular homeostasis dependence on MICU2, a regulatory subunit of the mitochondrial calcium uniporter.
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DOI：
10.1073/pnas.1711303114
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发表时间：
2017-10-24
影响因子：
11.1
通讯作者：
Seidman CE
中科院分区：
文献类型：
--
作者：
Bick AG;Wakimoto H;Kamer KJ;Sancak Y;Goldberger O;Axelsson A;DeLaughter DM;Gorham JM;Mootha VK;Seidman JG;Seidman CE
高血压增加了腹主动脉瘤的风险，这是一种无声的病理学，易于破裂并导致心脏性猝死。男性、吸烟和高血压似乎通过引起心血管组织中的氧化应激反应而增加腹主动脉瘤的发生风险。在这里，我们发现了线粒体钙单向转运蛋白的钙敏感调节亚基MICU 2和应激反应之间的意外联系。我们发现，幼稚Micu 2 −/−小鼠心脏舒张异常，但血压适度升高，发展为自发破裂的腹主动脉瘤。这些发现暗示线粒体钙稳态是保护心血管组织免受氧化应激的关键途径。对患有心血管疾病的人类和小鼠的转录谱的比较分析显示，MICU 2的表达持续升高，MICU 2是线粒体钙单向转运体复合物的调节亚基。为了确定MICU 2表达是否具有心脏保护作用，我们生产并表征了Micu 2-/-小鼠。突变小鼠左心房增大，Micu 2 −/−心肌细胞延迟肌节舒张和胞浆钙重摄取动力学，表明舒张功能障碍。Micu 2 −/−心室组织的RNA测序（RNA-seq）显示编码爱帕琳受体的转录物显著减少（Micu 2 −/− vs.野生型，P = 7.8 × 10−40），该受体通过变构反式抑制抑制血管紧张素II受体信号传导。我们发现，Micu 2 −/−和野生型小鼠的基础血压相当，对血管紧张素II输注的反应升高，但Micu 2 −/−小鼠表现出收缩功能障碍，腹主动脉破裂致死率为30%。去甲肾上腺素诱导的高血压未发生动脉瘤和破裂。Micu 2 −/−小鼠的主动脉组织细胞外基质重塑基因的表达增加，而单细胞RNA-seq分析显示，成纤维细胞和平滑肌细胞中与活性氧、炎症和增殖相关的基因表达增加。我们得出结论，Micu 2 −/−小鼠概括了舒张性心脏病的特征，并定义了Micu 2在调节血管紧张素II介导的高血压反应中以前未被认识到的作用，这些反应在保护腹主动脉免受损伤方面至关重要。
Hypertension increases the risk for development of abdominal aortic aneurysms, a silent pathology that is prone to rupture and cause sudden cardiac death. Male gender, smoking, and hypertension appear to increase risk for development of abdominal aortic aneurysms by provoking oxidative stress responses in cardiovascular tissues. Here we uncovered unexpected linkages between the calcium-sensing regulatory subunit MICU2 of the mitochondrial calcium uniporter and stress responses. We show that naive Micu2−/− mice had abnormalities of cardiac relaxation but, with modest blood pressure elevation, developed abdominal aortic aneurysms with spontaneous rupture. These findings implicate mitochondrial calcium homeostasis as a critical pathway involved in protecting cardiovascular tissues from oxidative stress. 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.
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影响因子：
20.1
作者：
Hofmann Bowman M;Wilk J;Heydemann A;Kim G;Rehman J;Lodato JA;Raman J;McNally EM
通讯作者：
McNally EM
影响因子：
16
作者：
Dong Z;Shanmughapriya S;Tomar D;Siddiqui N;Lynch S;Nemani N;Breves SL;Zhang X;Tripathi A;Palaniappan P;Riitano MF;Worth AM;Seelam A;Carvalho E;Subbiah R;Jaña F;Soboloff J;Peng Y;Cheung JY;Joseph SK;Caplan J;Rajan S;Stathopulos PB;Madesh M
通讯作者：
Madesh M
DOI：
10.1126/science.1214977
发表时间：
2012-05-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bick AG;Calvo SE;Mootha VK
通讯作者：
Mootha VK
影响因子：
15.9
作者：
Fentzke, RC;Korcarz, CE;Leiden, JM
通讯作者：
Leiden, JM
影响因子：
15.9
作者：
Chen, Peng-Chieh;Wakimoto, Hiroko;Kucherlapati, Raju
通讯作者：
Kucherlapati, Raju