Cardiac-specific BACH1 ablation attenuates pathological cardiac hypertrophy by inhibiting the Ang II type 1 receptor expression and the Ca2+/CaMKII pathway
Cardiac-specific BACH1 ablation attenuates pathological cardiac hypertrophy by inhibiting the Ang II type 1 receptor expression and the Ca2+/CaMKII pathway
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DOI：
10.1093/cvr/cvad086
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发表时间：
2023-06-03
影响因子：
10.8
通讯作者：
Meng, Dan
中科院分区：
文献类型：
--
作者：
Wei, Xiangxiang;Jin, Jiayu;Meng, Dan
目的BACH1在肥厚性心脏中表达上调，但其在肥厚性心脏中的功能尚不清楚。本研究探讨BACH1在心肌肥厚调控中的作用及机制。方法和结果雄性心脏特异性BACH1基因敲除小鼠或心脏特异性BACH1转基因（BACH1- tg）小鼠及其野生型仔鼠均发生血管紧张素II （Ang II）或主动脉横缩（TAC）诱导的心脏肥厚。小鼠心脏特异性BACH1敲除可保护心脏免受Ang II和tac诱导的心肌肥大和纤维化，并保留心功能。相反，在Ang II-和tac诱导的肥厚小鼠中，心脏特异性BACH1过表达明显加剧了心脏肥厚和纤维化，并降低了心功能。从机制上讲，BACH1沉默可以减弱Ang II和去甲肾上腺素刺激的钙/钙调素依赖性蛋白激酶II （CaMKII）信号传导、肥厚基因的表达和心肌细胞的肥厚生长。Ang II刺激促进BACH1的核定位，促进BACH1向Ang II型1受体（AT1R）基因启动子募集，进而增加AT1R的表达。抑制BACH1会减弱Ang ii刺激的AT1R表达、胞浆Ca2+水平和CaMKII在心肌细胞中的激活，而过表达BACH1则会导致相反的效果。CaMKII抑制剂KN93可抑制Ang II刺激后BACH1过表达引起的增生性基因表达增加。在体外实验中，AT1R拮抗剂氯沙坦显著减弱了Ang II刺激下bach1介导的CaMKII激活和心肌细胞肥大。同样地，氯沙坦治疗可减弱Angⅱ诱导的BACH1-Tg小鼠心肌病理性肥大、心肌纤维化和功能障碍。结论本研究阐明了BACH1通过调节AT1R表达和Ca2+/CaMKII通路在病理性心肌肥厚中的重要作用，并揭示了病理性心肌肥厚的潜在治疗靶点。
Aims BACH1 is up-regulated in hypertrophic hearts, but its function in cardiac hypertrophy remains largely unknown. This research investigates the function and mechanisms of BACH1 in the regulation of cardiac hypertrophy. Methods and results Male cardiac-specific BACH1 knockout mice or cardiac-specific BACH1 transgenic (BACH1-Tg) mice and their respective wild-type littermates developed cardiac hypertrophy induced by angiotensin II (Ang II) or transverse aortic constriction (TAC). Cardiac-specific BACH1 knockout in mice protected the hearts against Ang II- and TAC-induced cardiac hypertrophy and fibrosis, and preserved cardiac function. Conversely, cardiac-specific BACH1 overexpression markedly exaggerated cardiac hypertrophy and fibrosis and reduced cardiac function in mice with Ang II- and TAC-induced hypertrophy. Mechanistically, BACH1 silencing attenuated Ang II- and norepinephrine-stimulated calcium/calmodulin-dependent protein kinase II (CaMKII) signalling, the expression of hypertrophic genes, and hypertrophic growth of cardiomyocytes. Ang II stimulation promoted the nuclear localization of BACH1, facilitated the recruitment of BACH1 to the Ang II type 1 receptor (AT1R) gene promoter, and then increased the expression of AT1R. Inhibition of BACH1 attenuated Ang II-stimulated AT1R expression, cytosolic Ca2+ levels, and CaMKII activation in cardiomyocytes, whereas overexpression of BACH1 led to the opposite effects. The increased expression of hypertrophic genes induced by BACH1 overexpression upon Ang II stimulation was suppressed by CaMKII inhibitor KN93. The AT1R antagonist, losartan, significantly attenuated BACH1-mediated CaMKII activation and cardiomyocyte hypertrophy under Ang II stimulation in vitro. Similarly, Ang II-induced myocardial pathological hypertrophy, cardiac fibrosis, and dysfunction in BACH1-Tg mice were blunted by treatment with losartan. Conclusion This study elucidates a novel important role of BACH1 in pathological cardiac hypertrophy by regulating the AT1R expression and the Ca2+/CaMKII pathway, and highlights potential therapeutic target in pathological cardiac hypertrophy.