Apelin Is a Negative Regulator of Angiotensin II-Mediated Adverse Myocardial Remodeling and Dysfunction
Apelin Is a Negative Regulator of Angiotensin II-Mediated Adverse Myocardial Remodeling and Dysfunction
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Apelin 是血管紧张素 II 介导的不良心肌重塑和功能障碍的负调节剂
DOI：
10.1161/hypertensionaha.117.10156
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发表时间：
2017-12-01
期刊：
影响因子：
8.3
通讯作者：
Zhong, Jiu-Chang
中科院分区：
文献类型：
--
作者：
Zhang, Zhen-Zhou;Wang, Wang;Zhong, Jiu-Chang
爱帕琳途径已经成为心血管稳态和疾病的关键调节剂。然而，pyr 1-apelin-13在血管紧张素（Ang）II介导的心脏病中的确切作用仍不清楚。我们使用apelin缺陷（APLN（-/y））和载脂蛋白E基因敲除小鼠来评估pyr 1-apelin-13的调节作用。1岁APLN（-/y）小鼠出现心肌肥大和功能障碍，血管紧张素转换酶2水平降低。血管紧张素II输注（1.5 mg kg（-1）d（-1））4周可增强年轻APLN（-/y）心脏的氧化应激、病理性肥大和心肌纤维化，导致心功能障碍加重。重要的是，每日给予100 μ g/kg pyr 1-apelin-13导致血管紧张素转换酶2水平上调，超氧化物生成减少，肥大和纤维化相关基因表达减少，导致Ang II输注载脂蛋白E敲除小鼠心肌肥大、纤维化和功能障碍减弱。此外，pyr 1-apelin-13治疗通过激活Akt和内皮型一氧化氮合酶磷酸化信号在很大程度上减弱了载脂蛋白E基因敲除小鼠中Ang II诱导的细胞凋亡和超微结构损伤。在培养的新生大鼠心肌细胞和心脏成纤维细胞，血管紧张素II的曝光减少血管紧张素转换酶2蛋白和增加超氧化物生成，细胞增殖和迁移，这是拯救pyr 1-爱帕琳-13，Akt和内皮型一氧化氮合酶激动剂刺激。pyr 1-apelin-13显著地阻止了培养的心脏成纤维细胞中响应于Ang II的超氧化物生成和凋亡的增加，这通过与Akt抑制剂MK 2206的共处理而部分逆转。总之，pyr 1-apelin-13肽途径是衰老介导的和Ang II介导的不良心肌重塑和功能障碍的负性调节剂，代表了预防和治疗心脏病的潜在候选者。
The apelin pathway has emerged as a critical regulator of cardiovascular homeostasis and disease. However, the exact role of pyr1-apelin-13 in angiotensin (Ang) II-mediated heart disease remains unclear. We used apelin-deficient (APLN(-/y)) and apolipoprotein E knockout mice to evaluate the regulatory roles of pyr1-apelin-13. The 1-year aged APLN(-/y) mice developed myocardial hypertrophy and dysfunction with reduced angiotensin-converting enzyme 2 levels. Ang II infusion (1.5 mg kg(-1) d(-1)) for 4 weeks potentiated oxidative stress, pathological hypertrophy, and myocardial fibrosis in young APLN(-/y) hearts resulting in exacerbation of cardiac dysfunction. Importantly, daily administration of 100 mu g/kg pyr1-apelin-13 resulted in upregulated angiotensin-converting enzyme 2 levels, decreased superoxide production and expression of hypertrophy- and fibrosis-related genes leading to attenuated myocardial hypertrophy, fibrosis, and dysfunction in the Ang II-infused apolipoprotein E knockout mice. In addition, pyr1-apelin-13 treatment largely attenuated Ang II-induced apoptosis and ultrastructural injury in the apolipoprotein E knockout mice by activating Akt and endothelial nitric oxide synthase phosphorylation signaling. In cultured neonatal rat cardiomyocytes and cardiofibroblasts, exposure of Ang II decreased angiotensin-converting enzyme 2 protein and increased superoxide generation, cellular proliferation, and migration, which were rescued by pyr1-apelin-13, and Akt and endothelial nitric oxide synthase agonist stimulation. The increased superoxide generation and apoptosis in cultured cardiofibroblasts in response to Ang II were strikingly prevented by pyr1-apelin-13 which was partially reversed by cotreatment with the Akt inhibitor MK2206. In conclusion, pyr1-apelin-13 peptide pathway is a negative regulator of aging-mediated and Ang II-mediated adverse myocardial remodeling and dysfunction and represents a potential candidate to prevent and treat heart disease.