Zhang Jing, Cheng Yun-Jiu, Luo Chang-Jun, Yu Jia
Department of Cardiology, Liuzhou Municipal Liutie Central Hospital, Liuzhou, China.
Department of Cardiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Front Pharmacol. 2022 Aug 12;13:940365. doi: 10.3389/fphar.2022.940365. eCollection 2022.
Ectopic activation of renin-angiotensin-system contributes to cardiovascular and renal diseases. (Pro)renin receptor (PRR) binds to renin and prorenin, participating in the progression of nephrology. However, whether PRR could be considered as a therapeutic target for cardiac remodeling and heart failure remains unknown. Transverse aortic constriction (TAC) surgery was performed to establish a mouse model of chronic pressure overload-induced cardiac remodeling. Neonatal rat cardiomyocytes (CMs) and cardiac fibroblasts (CFs) were isolated and stimulated by Angiotensin II (Ang II). PRR decoy inhibitor PRO20 was synthesized and used to evaluate its effect on cardiac remodeling. Soluble PRR and PRR were significantly upregulated in TAC-induced cardiac remodeling and Ang II-treated CMs and CFs. Results of experiments showed that suppression of PRR by PRO20 significantly retarded cardiac remodeling and heart failure indicated by morphological and echocardiographic analyses. experiments, PRO20 inhibited CM hypertrophy, and also alleviated CF activation, proliferation and extracellular matrix synthesis. Mechanically, PRO20 enhanced intracellular cAMP levels, but not affected cGMP levels in CMs and CFs. Moreover, treatment of PRO20 in CFs markedly attenuated the production of reactive oxygen species and phosphorylation of IRE1 and PERK, two well-identified markers of endoplasmic reticulum (ER) stress. Accordingly, administration of PRO20 reversed ER stressor thapsigargin-induced CM hypertrophy and CF activation/migration. Taken together, these findings suggest that inhibition of PRR by PRO20 attenuates cardiac remodeling through increasing cAMP levels and reducing ER stress in both CMs and CFs.
肾素-血管紧张素系统的异位激活会导致心血管和肾脏疾病。（前体）肾素受体（PRR）与肾素和前肾素结合，参与肾脏病的进展。然而，PRR是否可被视为心脏重塑和心力衰竭的治疗靶点仍不清楚。进行横向主动脉缩窄（TAC）手术以建立慢性压力超负荷诱导的心脏重塑小鼠模型。分离新生大鼠心肌细胞（CMs）和心脏成纤维细胞（CFs），并用血管紧张素II（Ang II）刺激。合成PRR诱饵抑制剂PRO20并用于评估其对心脏重塑的影响。在TAC诱导的心脏重塑以及Ang II处理的CMs和CFs中，可溶性PRR和PRR显著上调。实验结果表明，PRO20对PRR的抑制作用显著延缓了形态学和超声心动图分析所示的心脏重塑和心力衰竭。实验中，PRO20抑制CM肥大，还减轻CF激活、增殖和细胞外基质合成。机制上，PRO20提高了CMs和CFs中的细胞内cAMP水平，但不影响cGMP水平。此外，在CFs中用PRO20处理可显著减弱活性氧的产生以及内质网（ER）应激的两个明确标志物IRE1和PERK的磷酸化。因此，给予PRO20可逆转ER应激剂毒胡萝卜素诱导的CM肥大和CF激活/迁移。综上所述，这些发现表明，PRO20对PRR的抑制作用通过提高cAMP水平和减轻CMs和CFs中的ER应激来减轻心脏重塑。
