Department of Cardiology, The 901st Hospital of the Joint Logistics Support Force of PLA, Hefei, China.
Rehabilitation Department, Lotus Lake Area the Red Cross in Xi'an City Hospital, Xi'an, China.
J Cardiovasc Pharmacol. 2022 Jul 1;80(1):125-131. doi: 10.1097/FJC.0000000000001292.
Homeodomain-interacting protein kinase-2 (HIPK2), a member of an evolutionary conserved family of serine/threonine kinases, has been observed to be involved in the pathogenesis of fibrotic diseases. However, its role in cardiac fibrosis remains unclear. In this study, we assessed the effect of HIPK2 on cardiac fibroblasts (CFs) in response to angiotensin II (Ang II) stimulation. The results indicated that HIPK2 expression was significantly increased in Ang II-induced CFs in a dose-dependent manner. Then, HIPK2 was knocked down in CFs to evaluate the roles of HIPK2. Knockdown of HIPK2 suppressed cell proliferation and migration in Ang II-induced CFs. The Ang II-caused increase in expression of α-smooth muscle actin, a hallmark of myofibroblast differentiation, was decreased by knockdown of HIPK2. HIPK2 knockdown also reduced extracellular matrix production including type I collagen and connective tissue growth factor. Furthermore, knockdown of HIPK2 blocked the activation of TGF-β1/Smad pathway in Ang II-induced CFs. These data suggested that HIPK2 knockdown prevented the Ang II-induced activation of CFs through inhibiting TGF-β1/Smad pathway, indicating HIPK2 might be an antifibrosis target for the treatment of cardiac fibrosis.
同源结构域相互作用蛋白激酶-2（HIPK2）是进化上保守的丝氨酸/苏氨酸激酶家族的一员，其被观察到参与纤维化疾病的发病机制。然而，其在心脏纤维化中的作用尚不清楚。在这项研究中，我们评估了 HIPK2 对血管紧张素 II（Ang II）刺激后的心脏成纤维细胞（CFs）的影响。结果表明，HIPK2 的表达在 Ang II 诱导的 CFs 中呈剂量依赖性显著增加。然后，在 CFs 中敲低 HIPK2 以评估 HIPK2 的作用。敲低 HIPK2 抑制了 Ang II 诱导的 CFs 的增殖和迁移。HIPK2 敲低还降低了 Ang II 引起的α-平滑肌肌动蛋白（一种肌成纤维细胞分化的标志）表达的增加。HIPK2 敲低还减少了包括 I 型胶原和结缔组织生长因子在内的细胞外基质的产生。此外，HIPK2 敲低阻断了 Ang II 诱导的 CFs 中 TGF-β1/Smad 通路的激活。这些数据表明，HIPK2 敲低通过抑制 TGF-β1/Smad 通路阻止了 Ang II 诱导的 CFs 的激活，表明 HIPK2 可能是治疗心脏纤维化的抗纤维化靶标。
