Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes.
Regulation of Smooth Muscle Cell Proliferation by Mitochondrial Ca2+ in Type 2 Diabetes.
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DOI：
10.3390/ijms241612897
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发表时间：
2023-08-17
影响因子：
5.6
通讯作者：
Grumbach, Isabella M.
中科院分区：
文献类型：
--
作者：
Koval, Olha M.;Nguyen, Emily K.;Mittauer, Dylan J.;Ait-Aissa, Karima;Chinchankar, William C.;Grumbach, Isabella M.
2型糖尿病（T2 D）与血管平滑肌细胞（VSMC）过度增殖导致的动脉粥样硬化性血管疾病风险增加相关。在这里，我们研究了线粒体功能障碍和Ca 2+水平在T2 D VSMC增殖中的作用。从正常血糖和饮食诱导的T2 D样小鼠中分离VSMC。使用选择性抑制VSMCs中线粒体Ca 2 +/钙调素依赖性激酶II（mtCaMKII）的小鼠研究线粒体Ca 2+摄取的影响。使用ER-000444793封闭线粒体转换孔（mPTP）。与血糖正常小鼠相比，T2 D小鼠的VSMC表现出增殖和基线胞质Ca 2+水平（[Ca 2 +]cyto）增加。T2 D细胞显示较低的内质网Ca 2+水平，减少线粒体Ca 2+进入，并增加Ca 2+泄漏通过mPTP。血小板源性生长因子（PDGF）给药后，T2 D细胞线粒体和胞浆Ca 2+瞬变减少。抑制线粒体Ca ~（2+）摄取或mPTP可降低T2 D VSMC增殖，但对[Ca ~（2+）]细胞有相反的影响。在T2 D VSMCs中，观察到Erk 1/2及其上游调节因子的激活增强，由升高的[Ca 2 +]细胞内Ca 2+驱动。抑制mtCaMKII通过阻断线粒体Ca 2+进入而使Ca 2+失衡恶化，导致[Ca 2 +]cyto和Erk 1/2超活化进一步增加。在此条件下，PDGF对VSMC增殖无影响。抑制胞浆中的Ca 2+依赖性信号传导减少了Erk 1/2的过度激活和VSMC增殖。我们的研究结果表明，改变Ca 2+处理驱动增强VSMC增殖T2 D，线粒体功能障碍有助于这一过程。
Type 2 diabetes (T2D) is associated with increased risk of atherosclerotic vascular disease due to excessive vascular smooth muscle cell (VSMC) proliferation. Here, we investigated the role of mitochondrial dysfunction and Ca2+ levels in VSMC proliferation in T2D. VSMCs were isolated from normoglycemic and T2D-like mice induced by diet. The effects of mitochondrial Ca2+ uptake were studied using mice with selectively inhibited mitochondrial Ca2+/calmodulin-dependent kinase II (mtCaMKII) in VSMCs. Mitochondrial transition pore (mPTP) was blocked using ER-000444793. VSMCs from T2D compared to normoglycemic mice exhibited increased proliferation and baseline cytosolic Ca2+ levels ([Ca2+]cyto). T2D cells displayed lower endoplasmic reticulum Ca2+ levels, reduced mitochondrial Ca2+ entry, and increased Ca2+ leakage through the mPTP. Mitochondrial and cytosolic Ca2+ transients were diminished in T2D cells upon platelet-derived growth factor (PDGF) administration. Inhibiting mitochondrial Ca2+ uptake or the mPTP reduced VSMC proliferation in T2D, but had contrasting effects on [Ca2+]cyto. In T2D VSMCs, enhanced activation of Erk1/2 and its upstream regulators was observed, driven by elevated [Ca2+]cyto. Inhibiting mtCaMKII worsened the Ca2+ imbalance by blocking mitochondrial Ca2+ entry, leading to further increases in [Ca2+]cyto and Erk1/2 hyperactivation. Under these conditions, PDGF had no effect on VSMC proliferation. Inhibiting Ca2+-dependent signaling in the cytosol reduced excessive Erk1/2 activation and VSMC proliferation. Our findings suggest that altered Ca2+ handling drives enhanced VSMC proliferation in T2D, with mitochondrial dysfunction contributing to this process.
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影响因子：
8
作者：
Baksh, S;DeCaprio, JA;Burakoff, SJ
通讯作者：
Burakoff, SJ
DOI：
10.1152/ajpheart.00932.2010
发表时间：
2011-01-01
影响因子：
4.8
作者：
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通讯作者：
Kypson, Alan P.
影响因子：
9.3
作者：
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通讯作者：
Erickson JR
影响因子：
21.3
作者：
Baines, Christopher P.;Kaiser, Robert A.;Molkentin, Jeffery D.
通讯作者：
Molkentin, Jeffery D.
影响因子：
4.3
作者：
Abhijit, Shiny;Bhaskaran, Regin;Balasubramanyam, Muthuswamy
通讯作者：
Balasubramanyam, Muthuswamy