Perillyl alcohol attenuates hypoxia induced right ventricular dysfunction and remodeling by balancing the renin angiotensin aldosterone system in rats

Hypoxia induced-pulmonary hypertension (HPH) is a life-threatening cardiovascular disorder prevalent in high-altitude regions. Right ventricular (RV) function and RV—pulmonary arterial (RV—PA) coupling are key to patient prognosis. Perillyl alcohol (POH), a natural compound, holds promise for managing pulmonary arterial hypertension (PAH). This study established HPH rat models via hypobaric chamber simulation (5000 m altitude) to explore the impact of POH on RV structure and function. Using a multi-modal approach, we employed echocardiography to assess RV function and RV-PA coupling. HE and Masson’s trichrome staining for tissue morphology and fibrosis. Immunohistochemistry, immunofluorescence, and western blotting to quantify collagen I/III and α-SMA. MDA, GSH, SOD, GSH-PX, IL-6 and TNF-α levels were measured using their respective commercial kits. ELISA/western blotting to analyze the ACE-Ang II-AT1R and ACE2-Ang (1–7)-MAS axes. Results showed that POH significantly restored RV function and RV-PA coupling, outperforming sildenafil in reducing RV structural changes (RVID-D, RVID-S, RVFT-D, RVFT-S). It normalized hypoxia-elevated hematological parameters (HCT, HGB, RBC), alleviated cardiomyocyte hypertrophy, fibrosis and inflammatory, and reversed RV remodeling. Mechanistically, POH exerted antioxidant effects and modulated the renin–angiotensin–aldosterone system (RAAS), decreasing ACE, Ang II, and AT1R levels while increasing ACE2, Ang (1–7), and MAS expression. In conclusion, POH improves RV function, preserves RV-PA coupling, and reduces RV systolic pressure, indicating its potential as an effective therapy for PAH patients.