α-Phellandrene attenuates the right ventricular structure and function in HPH rats via the NO-sGC-cGMP pathway

Right ventricular (RV) dysfunction is a pivotal prognostic determinant in patients with pulmonary arterial hypertension (PAH). Hypoxic stimulation induces hypoxic pulmonary vasoconstriction (HPV) and exerts cardiotoxic effects, thereby accelerating RV remodeling in PAH. Previous in vitro vascular ring experiments demonstrated that α-phellandrene (PE) exhibits vasodilatory effects, but its impact on hypoxia-induced RV structural and functional alterations and underlying mechanisms remain unclear. To address this, we established a hypoxia-induced pulmonary arterial hypertension (HPH) rats model and comprehensively evaluated the therapeutic effects of PE on multi-scale RV pathological remodeling through echocardiography, histomorphometric analyses, and Western blot. Additionally, the molecular mechanisms underlying PE-mediated modulation of the nitric oxide (NO)-soluble guanylyl cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway were investigated using H9C2 cardiomyocytes. Results demonstrated that compared with the model group, PE treatment significantly improved RV systolic function in HPH rats, as evidenced by increased tricuspid annular plane systolic excursion, pulmonary artery acceleration time, fractional area change, and RV ejection fraction. Concurrently, PE reduced RV free wall thickness in diastole and RV inner diameter, effectively attenuating hypoxia-induced RV remodeling. PE administration also markedly decreased mean pulmonary artery pressure and RV hypertrophy index compared to the model group. Histomorphological analysis demonstrated that PE treatment significantly reduced collagen deposition in RV tissues and downregulated expression of fibrotic markers, including α-smooth muscle actin, collagen Ⅰ and collagen Ⅲ. Mechanistic investigations revealed that PE upregulated endothelial nitric oxide synthase expression in both rats RV tissues and H9C2 cardiomyocytes, enhanced NO bioavailability, and activated sGC- cGMP signaling axis. These molecular effects collectively ameliorated hypoxia-induced oxidative damage and attenuated fibrotic progression. This study reveals that PE ameliorates hypoxia-induced RV remodeling and dysfunction by modulating the NO-sGC-cGMP signaling pathway to reduce oxidative damage and fibrotic remodeling in hypoxic conditions. These findings provide experimental evidence for developing RV-targeted therapeutic strategies against HPH. All animal experiments were approved by the Institutional Animal Care and Use Committee of Qinghai University (approval No: PJ-202302-01).