Amplifying effect of chronic lisinopril therapy on diastolic function and the angiotensin-(1-7) Axis by the G1 agonist in ovariectomized spontaneously hypertensive rats
Translational research : the journal of laboratory and clinical medicine(2021)
摘要
G protein-coupled estrogen receptor (GPER) activation by G1 attenuates diastolic dysfunction from estrogen loss, which may be partly due to suppression of angiotensin II pathological actions. We aimed to determine the independent effects of 8 weeks of G1 (100 mg/kg/d, subcutaneous pellet), ACE-inhibition (ACEi; lisinopril 10 mg/kg, drinking water), or combination therapy versus vehicle in the ovariectomized (OVX) spontaneously hypertensive rat (SHR) on cardiac function and morphometrics (echocardiography), serum equilibrium of angiotensins (mass spectroscopy) and cardiac components of the RAS (Western blotting). G1 alone and when combined with ACEi enhanced myocardial relaxation (e: 30 and 17%) and diastolic wall strain (DWS: 76 and 68%) while reducing relative wall thickness (RWT: 20 and 33%) and filling pressures (E/e: 30 and 37%). Cardiac expression levels of Mas receptor (Mas-R) and ACE2 also increased in the presence of G1. Strong antihypertensive effects of lisinopril monotherapy were associated with reductions in RWT, collagen deposition and E/ewithout overtly altering eor DWS. Chronic ACEi also increased cardiac levels of Mas-R and AT1-R and tilted the circulating RAS toward the formation of Ang-(1-7), which was amplified in the presence of G1. In vitro studies further revealed that an inhibitor to prolyl endopeptidase (PEP), but not to neprilysin, significantly reduced serum Ang-(1-7) levels in G1-treated rats, suggesting that G1 might be increasing Ang-(1-7) formation via PEP. We conclude that activating GPER with G1 augments components of the cardiac RAS and improves diastolic function without lowering blood pressure, and that lisinopril-induced blood pressure control and cardiac alterations in OVX SHR are permissive in facilitating G1 to augment Ang-(1-7) in serum, thereby strengthening its cardioprotective benefits. (Translational Research 2021; 235:62-76)
更多查看译文
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要