Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling.
Elevated MCU Expression by CaMKIIδB Limits Pathological Cardiac Remodeling.
复制标题
CaMKIIδB升高MCU表达限制病理性心脏重构
DOI：
10.1161/circulationaha.121.055841
复制
发表时间：
2022-04-05
期刊：
影响因子：
37.8
通讯作者：
Wang W
中科院分区：
文献类型：
--
作者：
Wang P;Xu S;Xu J;Xin Y;Lu Y;Zhang H;Zhou B;Xu H;Sheu SS;Tian R;Wang W
钙(Ca~(2+))是能量代谢的关键调节因子。钙稳态受损会损害线粒体，导致心肌细胞死亡、病理性肥大和心力衰竭。本研究探讨线粒体钙离子单一转运体(MCU)在慢性应激诱导的病理性心脏重构中的调控和作用。对MCU基因敲除或转基因小鼠给予异丙肾上腺素(ISO，10 mg/kg/d，4周)。超声心动图和组织学检查评价心肌肥厚和重构。原代培养的成年啮齿动物心肌细胞用ISO(1 NM，48小时)处理。监测细胞内钙离子的处理和细胞死亡途径。体外用腺病毒介导的基因操作。体内和体外长期给予β-肾上腺素能受体(β-AR)激动剂ISO均可增加心肌线粒体mcu和mcu复合体的水平，从而提高线粒体的钙离子浓度。ISO还上调了MCU的表达，但不影响其在成年心肌细胞中的调节蛋白。有趣的是，在全球MCU基因敲除(KO)小鼠中，ISO诱导的心肌肥大、纤维化、收缩功能障碍和心肌细胞死亡加剧。来自KO小鼠或过度表达显性阴性MCU的小鼠的心肌细胞表现出细胞内钙处理和激活多个细胞死亡途径的缺陷。相反，心脏特异的MCU过表达维持细胞内钙稳态和收缩能力，抑制细胞死亡，并防止ISO诱导的心肌肥大。Iso通过激活钙/钙调蛋白激酶IIδB(CaMKIIδB)并通过钙调神经磷酸酶介导的丝氨酸332去磷酸化促进其核转位来上调MCU的表达。核内CaMKIIδB磷酸化cAMP反应元件结合蛋白，结合mcu启动子，增强mcu基因转录。β-AR/CaMKII-δB/CREB途径上调心脏Mcu基因表达。MCU上调是一种代偿机制，通过维持钙稳态和心肌细胞活性来对抗应激诱导的病理性心脏重构。
Calcium (Ca2+) is a key regulator of energy metabolism. Impaired Ca2+ homeostasis damages mitochondria, causing cardiomyocyte death, pathological hypertrophy, and heart failure. This study investigates the regulation and the role of the mitochondrial Ca2+ uniporter (MCU) in chronic stress-induced pathological cardiac remodeling. MCU knockout or transgenic mice were infused with isoproterenol (ISO, 10 mg/kg/day, 4 weeks). Cardiac hypertrophy and remodeling were evaluated by echocardiography and histology. Primary cultured rodent adult cardiomyocytes were treated with ISO (1 nM, 48 hr). Intracellular Ca2+ handling and cell death pathways were monitored. Adenovirus-mediated gene manipulations were used in vitro. Chronic administration of the β-adrenergic receptor (β-AR) agonist ISO increased the levels of the MCU and the MCU complex in cardiac mitochondria, raising mitochondrial Ca2+ concentrations, in vivo and in vitro. ISO also upregulated MCU without affecting its regulatory proteins in adult cardiomyocytes. Interestingly, ISO-induced cardiac hypertrophy, fibrosis, contractile dysfunction, and cardiomyocyte death were exacerbated in global MCU knockout (KO) mice. Cardiomyocytes from KO mice or mice overexpressing a dominant negative MCU exhibited defective intracellular Ca2+ handling and activation of multiple cell death pathways. Conversely, cardiac-specific overexpression of MCU maintained intracellular Ca2+ homeostasis and contractility, suppressed cell death, and prevented ISO-induced heart hypertrophy. ISO upregulated MCU expression through activation of Ca2+/calmodulin kinase II δB (CaMKIIδB) and promotion of its nuclear translocation via calcineurin-mediated dephosphorylation at serine 332. Nuclear CaMKIIδB phosphorylated cAMP-response element binding protein (CREB), which bound the MCU promotor to enhance MCU gene transcription. The β-AR/CaMKIIδB/CREB pathway upregulates MCU gene expression in the heart. MCU upregulation is a compensatory mechanism that counteracts stress-induced pathological cardiac remodeling by preserving Ca2+ homeostasis and cardiomyocyte viability.