Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Fraternal Order of Eagles Diabetes Research Center, Division of Endocrinology and Metabolism, Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.
Int J Mol Sci. 2023 Aug 17;24(16):12897. doi: 10.3390/ijms241612897.
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.
2 型糖尿病（T2D）与动脉粥样硬化血管疾病风险增加有关，这是由于血管平滑肌细胞（VSMC）过度增殖所致。在这里，我们研究了线粒体功能障碍和 Ca2+水平在 T2D 中 VSMC 增殖中的作用。从正常血糖和饮食诱导的 T2D 样小鼠中分离出 VSMCs。使用在 VSMCs 中选择性抑制线粒体 Ca2+/钙调蛋白依赖性激酶 II（mtCaMKII）的小鼠研究了线粒体 Ca2+摄取的影响。使用 ER-000444793 阻断线粒体通透性转换孔（mPTP）。与正常血糖小鼠相比，T2D 小鼠的 VSMCs 增殖和基础细胞浆 Ca2+水平（[Ca2+]cyto）增加。T2D 细胞显示内质网 Ca2+水平较低，线粒体 Ca2+内流减少，mPTP 通过 Ca2+渗漏增加。血小板衍生生长因子（PDGF）给药后，T2D 细胞的线粒体和细胞质 Ca2+瞬变减少。在 T2D 中，抑制线粒体 Ca2+摄取或 mPTP 可减少 VSMC 增殖，但对 [Ca2+]cyto 有相反的影响。在 T2D VSMCs 中，观察到 Erk1/2 及其上游调节剂的活性增强，这是由细胞浆 Ca2+水平升高驱动的。抑制 mtCaMKII 通过阻断线粒体 Ca2+内流使 Ca2+失衡恶化，导致 [Ca2+]cyto 和 Erk1/2 过度激活进一步增加。在这些条件下，PDGF 对 VSMC 增殖没有影响。抑制细胞质中 Ca2+依赖性信号转导可减少过度的 Erk1/2 激活和 VSMC 增殖。我们的研究结果表明，改变的 Ca2+处理驱动 T2D 中增强的 VSMC 增殖，线粒体功能障碍对此过程有贡献。
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