Department of Anesthesiology, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
J Am Heart Assoc. 2018 Jan 22;7(2):e005696. doi: 10.1161/JAHA.117.005696.
Severe cardiac hypertrophy can lead to cardiac remodeling and even heart failure in the end, which is a leading cause of cardiovascular disease-related mortality worldwide. A disintegrin and metalloprotease-22 (ADAM22), a member of the transmembrane and secreted metalloendopeptidase family, participates in many biological processes, including those in the cardiovascular system. However, there is no explicit information on whether ADAM22 can regulate the process of cardiac hypertrophy; the effects that ADAM22 exerts in cardiac hypertrophy remain elusive.
We observed significantly increased ADAM22 expression in failing hearts from patients with dilated cardiomyopathy and hypertrophic cardiomyopathy; the same trend was observed in mice induced by transaortic constriction and in neonatal rat cardiomyocytes treated by angiotensin II. Therefore, we constructed both cardiac-specific ADAM22 overexpression and knockout mice. At 4 weeks after transaortic constriction, cardiac-specific ADAM22 knockout, by the CRISPR/Cas9 (clustered regularly interspaced palindromic repeat (CRISPR)-Cas9) system, deteriorated the severity of cardiac hypertrophy in mice, whereas cardiac-specific ADAM22 overexpression mitigated the degrees of cardiac hypertrophy in mice. Similarly, altered ADAM22 expression modulated the angiotensin II-mediated cardiomyocyte hypertrophy in neonatal rat cardiomyocytes. After screening several signaling pathways, we found ADAM22 played a role in inhibition of protein kinase B (AKT) activation. Under the cardiac-specific ADAM22 knockout background, AKT activation was enhanced in transaortic constriction-induced mice and angiotensin II-stimulated neonatal rat cardiomyocytes, with a severe degree of cardiac hypertrophy. Treatment of a specific AKT inhibitor attenuated the transaortic constriction-enhanced AKT activation and cardiac hypertrophy in mice.
The findings demonstrated that ADAM22 negatively regulates the AKT activation and the process of cardiac hypertrophy and may provide new insights into the pathobiological features of cardiac hypertrophy.
严重的心肌肥厚可导致心肌重构，甚至最终心力衰竭，这是全球心血管疾病相关死亡的主要原因。解整合素金属蛋白酶 22（ADAM22）是跨膜和分泌金属内肽酶家族的成员，参与包括心血管系统在内的许多生物学过程。然而，目前尚无明确信息表明 ADAM22 是否可以调节心肌肥厚过程；ADAM22 在心肌肥厚中的作用仍不清楚。
我们观察到扩张型心肌病和肥厚型心肌病患者衰竭心脏中 ADAM22 的表达显著增加；同样的趋势也在主动脉缩窄诱导的小鼠和血管紧张素 II 处理的新生大鼠心肌细胞中观察到。因此，我们构建了心脏特异性 ADAM22 过表达和敲除小鼠。主动脉缩窄 4 周后，CRISPR/Cas9（成簇规律间隔短回文重复（CRISPR）-Cas9）系统敲除心脏特异性 ADAM22 加重了小鼠的心肌肥厚程度，而心脏特异性 ADAM22 过表达减轻了小鼠的心肌肥厚程度。同样，改变 ADAM22 表达可调节血管紧张素 II 介导的新生大鼠心肌细胞肥大。在筛选了几种信号通路后，我们发现 ADAM22 参与了蛋白激酶 B（AKT）激活的抑制。在心脏特异性 ADAM22 敲除背景下，主动脉缩窄诱导的小鼠和血管紧张素 II 刺激的新生大鼠心肌细胞中的 AKT 激活增强，心肌肥厚程度严重。特异性 AKT 抑制剂的治疗可减弱主动脉缩窄增强的 AKT 激活和小鼠的心肌肥厚。
这些发现表明 ADAM22 负性调节 AKT 激活和心肌肥厚过程，可能为心肌肥厚的病理生物学特征提供新的见解。
