Xu Lei, Han Shasha, Chen Zhaoyang, Shen Cheng, Yao Zihan, Wang Peng, Zou Yunzeng, Sun Aijun, Ge Junbo
Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 200032 Shanghai, China.
Intensive Care Unit, Jining First People's Hospital, 272002 Jining, Shandong, China.
Rev Cardiovasc Med. 2022 Apr 2;23(4):127. doi: 10.31083/j.rcm2304127. eCollection 2022 Apr.
Both epidemiologic and experimental studies have evidenced that chronic kidney disease (CKD) could increase the incidence and risk of cardiac dysfunction, especially in aging patients. However, the underlying mechanisms are still not fully understood.
In this study, we used 8 weeks old male wild-type (WT) C57BL/6 mice and ALDH2 knockout (ALDH2-/-) mice with C57BL/6 background. Here the 5/6 nephrectomy (NX) mouse model was constructed to study how CKD affects cardiac function and explored the related role of aldehyde dehydrogenase 2 (ALDH2), a well-established cardioprotective factor, in this process.
Compensatory cardiac hypertrophy was found in wild type (WT) mice 12 weeks post 5/6 NX as shown by increased left ventricular wall thickness (LVWD), cross-sectional area (CSA) of cardiomyocytes, and preserved left ventricular ejection fraction (EF) and fractional shorten (FS). Deficiency of ALDH2 (ALDH2-/-) significantly reduced EF and FS as compared with WT mice 12 weeks post 5/6 NX, while left ventricular hypertrophy was similar between the two NX groups. ALDH2-/- CKD groups showed more severe nephritic damages and increased fibrosis deposition in hearts. Besides, levels of reactive oxygen species (ROS) and apoptosis were also significantly upregulated in hearts of ALDH2-/- NX mice. The above changes were related with decreased expressions of uncoupling protein 2 (UCP2) and nuclear factor like 2 (Nrf2), as well as the downstream effectors of Nrf2 (heme oxygenase-1, HO-1 and superoxide dismutase 2, SOD2).
Our data indicated that ALDH2 deficiency did not affect NX-induced left ventricular hypertrophy, but could increase oxidative stress and exacerbate CKD-induced cardiac dysfunction, partly via downregulation of UCP2 and Nrf2/ARE (antioxidant response element) pathways.
流行病学和实验研究均已证明，慢性肾脏病（CKD）会增加心脏功能障碍的发生率和风险，尤其是在老年患者中。然而，其潜在机制仍未完全明确。
在本研究中，我们使用了8周龄的雄性野生型（WT）C57BL/6小鼠和具有C57BL/6背景的乙醛脱氢酶2基因敲除（ALDH2-/-）小鼠。构建5/6肾切除（NX）小鼠模型以研究CKD如何影响心脏功能，并探讨已被充分证实的心脏保护因子乙醛脱氢酶2（ALDH2）在此过程中的相关作用。
5/6肾切除术后12周，野生型（WT）小鼠出现代偿性心脏肥大，表现为左心室壁厚度（LVWD）增加、心肌细胞横截面积（CSA）增大，且左心室射血分数（EF）和缩短分数（FS）保持正常。与5/6肾切除术后12周的WT小鼠相比，ALDH2缺乏（ALDH2-/-）显著降低了EF和FS，而两组肾切除小鼠的左心室肥大情况相似。ALDH2-/-CKD组显示出更严重的肾脏损伤以及心脏中纤维化沉积增加。此外，ALDH2-/-肾切除小鼠心脏中的活性氧（ROS）水平和细胞凋亡也显著上调。上述变化与解偶联蛋白2（UCP2）和核因子样2（Nrf2）以及Nrf2的下游效应分子（血红素加氧酶-1，HO-1和超氧化物歧化酶2，SOD2）的表达降低有关。
我们的数据表明，ALDH2缺乏并不影响肾切除诱导的左心室肥大，但可增加氧化应激并加重CKD诱导的心脏功能障碍，部分原因是通过下调UCP2和Nrf2/抗氧化反应元件（ARE）途径。
