Wang Wang, Patel Vaibhav B, Parajuli Nirmal, Fan Dong, Basu Ratnadeep, Wang Zuocheng, Ramprasath Tharmarajan, Kassiri Zamaneh, Penninger Josef M, Oudit Gavin Y
Division of Cardiology, Department of Medicine, Mazankowski Alberta Heart Institute, University of Alberta, Edmonton, AB, T6G 2S2, Canada.
J Mol Med (Berl). 2014 Aug;92(8):847-58. doi: 10.1007/s00109-014-1149-y. Epub 2014 Apr 15.
Angiotensin-converting enzyme 2 (ACE2) metabolizes Ang II into Ang 1-7 thereby negatively regulating the renin-angiotensin system. However, heart disease in humans and in animal models is associated with only a partial loss of ACE2. ACE2 is an X-linked gene; and as such, we tested the clinical relevance of a partial loss of ACE2 by using female ACE2(+/+) (wildtype) and ACE2(+/-) (heterozygote) mice. Pressure overload in ACE2(+/-) mice resulted in greater LV dilation and worsening systolic and diastolic dysfunction. These changes were associated with increased myocardial fibrosis, hypertrophy, and upregulation of pathological gene expression. In response to Ang II infusion, there was increased NADPH oxidase activity and myocardial fibrosis resulting in the worsening of Ang II-induced diastolic dysfunction with a preserved systolic function. Ang II-mediated cellular effects in cultured adult ACE2(+/-) cardiomyocytes and cardiofibroblasts were exacerbated. Ang II-mediated pathological signaling worsened in ACE2(+/-) hearts characterized by an increase in the phosphorylation of ERK1/2 and JNK1/2 and STAT-3 pathways. The ACE2(+/-) mice showed an exacerbated pressor response with increased vascular fibrosis and stiffness. Vascular superoxide and nitrotyrosine levels were increased in ACE2(+/-) vessels consistent with increased vascular oxidative stress. These changes occurred with increased renal fibrosis and superoxide production. Partial heterozygote loss of ACE2 is sufficient to increase the susceptibility to heart disease secondary to pressure overload and Ang II infusion.
Heart disease in humans with idiopathic dilated cardiomyopathy is associated with a partial loss of ACE2. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to pressure overload-induced heart disease. Heterozygote female ACE2 mutant mice showed enhanced susceptibility to Ang II-induced heart and vascular diseases. Partial loss of ACE2 is sufficient to enhance the susceptibility to heart disease.
血管紧张素转换酶2（ACE2）将血管紧张素II（Ang II）代谢为血管紧张素1-7，从而对肾素-血管紧张素系统起负调节作用。然而，人类和动物模型中的心脏病仅与ACE2的部分缺失有关。ACE2是一个X连锁基因；因此，我们通过使用雌性ACE2(+/+)（野生型）和ACE2(+/-)（杂合子）小鼠来测试ACE2部分缺失的临床相关性。ACE2(+/-)小鼠的压力超负荷导致左心室扩张更严重，收缩和舒张功能障碍恶化。这些变化与心肌纤维化、肥大增加以及病理基因表达上调有关。在输注Ang II后，NADPH氧化酶活性增加和心肌纤维化导致Ang II诱导的舒张功能障碍恶化，而收缩功能保留。Ang II介导的成年ACE2(+/-)心肌细胞和成纤维细胞中的细胞效应加剧。在ACE2(+/-)心脏中，Ang II介导的病理信号传导恶化，其特征是ERK1/2、JNK1/2和STAT-3途径的磷酸化增加。ACE2(+/-)小鼠表现出升压反应加剧，血管纤维化和僵硬增加。ACE2(+/-)血管中的血管超氧化物和硝基酪氨酸水平升高，与血管氧化应激增加一致。这些变化伴随着肾纤维化和超氧化物产生增加。ACE2的部分杂合子缺失足以增加对压力超负荷和Ang II输注继发的心脏病的易感性。
特发性扩张型心肌病患者的心脏病与ACE2的部分缺失有关。杂合子雌性ACE2突变小鼠对压力超负荷诱导的心脏病易感性增强。杂合子雌性ACE2突变小鼠对Ang II诱导的心脏和血管疾病易感性增强。ACE2的部分缺失足以增强对心脏病的易感性。
