Koval Olha M, Nguyen Emily K, Mittauer Dylan J, Buchanan Jane L, Westhoff Kyle, Dai Dao-Fu, Taylor Eric B, Grumbach Isabella M
Abboud Cardiovascular Research Center, Division of Cardiovascular Medicine, Department of Internal Medicine, Carver College of Medicine University of Iowa Iowa City IA USA.
Department of Molecular Physiology and Biophysics University of Iowa Carver College of Medicine Iowa City IA USA.
J Am Heart Assoc. 2025 Jul 17:e039220. doi: 10.1161/JAHA.124.039220.
Excessive proliferation of vascular smooth muscle cells (VSMCs) is a consequence of type 2 diabetes (T2D) that increases the risk for atherosclerosis and restenosis after angioplasty. Here, we sought to determine whether and how mitochondrial dysfunction in T2D drives VSMC proliferation with a focus on increased reactive oxygen species and intracellular [Ca] that both drive cell proliferation, occur in T2D, and are regulated by the mitochondrial Ca uniporter (MCU).
Using a mouse model of T2D, we performed in vivo phenotyping after mechanical injury and established the mechanisms of excessive proliferation in cultured VSMCs. The T2D model was induced by high-fat diet and low-dose streptozotocin in both wild type mice and mice with the VSMC-specific inhibition of the mtCaMKII (mitochondrial Ca/calmodulin-dependent kinase IImtCaMKII), a regulator of Ca entry via the MCU.
In VSMCs from T2D model mice, MCU inhibition reduced both in vivo neointima formation after mechanical injury, as well as in vitro proliferation of cultured VSMCs. Further, in VSMCs from T2D mice, the composition of the MCU complex and MCU activity were altered with loss of MICU1 (mitochondrial calcium uptake 1). In addition, VSMC mitochondrial reactive oxygen species was elevated and mitochondrial respiration blunted. The increase in cytosolic reactive oxygen species induced activation of G6PD (glucose-6-phosphate dehydrogenase), a key enzyme of the pentose phosphate pathway. However, inhibiting MCU or MICU1 overexpression on VSMCs from T2D mice decreased intracellular reactive oxygen species, preserved mitochondrial respiration and ATP production, decreased activity of G6PD, and normalized cell proliferation. These data suggest the MCU complex controls a T2D-induced metabolic switch that promotes cell proliferation.
Collectively, these data indicate that MCU complex remodeling in T2D drives neointimal restenosis, suggesting MCU as a therapeutic target.
血管平滑肌细胞（VSMC）过度增殖是2型糖尿病（T2D）的一个后果，会增加动脉粥样硬化和血管成形术后再狭窄的风险。在此，我们试图确定T2D中的线粒体功能障碍是否以及如何驱动VSMC增殖，重点关注增加的活性氧（ROS）和细胞内钙离子浓度（[Ca]），这两者都驱动细胞增殖，在T2D中出现，并由线粒体钙单向转运体（MCU）调节。
使用T2D小鼠模型，我们在机械损伤后进行了体内表型分析，并确定了培养的VSMC中过度增殖的机制。通过高脂饮食和低剂量链脲佐菌素在野生型小鼠和特异性抑制mtCaMKII（线粒体钙/钙调蛋白依赖性激酶II）的VSMC的小鼠中诱导T2D模型，mtCaMKII是通过MCU进入钙离子的调节剂。
在T2D模型小鼠的VSMC中，抑制MCU可减少机械损伤后的体内新生内膜形成以及培养的VSMC的体外增殖。此外，在T2D小鼠的VSMC中，MCU复合物的组成和MCU活性随着MICU1（线粒体钙摄取蛋白1）的缺失而改变。另外，VSMC线粒体ROS升高，线粒体呼吸减弱。胞质ROS的增加诱导了磷酸戊糖途径的关键酶G6PD（葡萄糖-6-磷酸脱氢酶）的激活。然而，抑制T2D小鼠VSMC上的MCU或过表达MICU1可降低细胞内ROS，保留线粒体呼吸和ATP产生，降低G6PD活性，并使细胞增殖正常化。这些数据表明MCU复合物控制了T2D诱导的促进细胞增殖的代谢转换。
总体而言，这些数据表明T2D中MCU复合物重塑驱动新生内膜再狭窄，提示MCU作为一个治疗靶点。
