Fenofibrate as a Modulator of the Renin–Angiotensin System in Su/Hx-Induced Pulmonary Arterial Hypertension

We evaluated the effects of fenofibrate (FF) in a SU5416/hypoxia model of pulmonary arterial hypertension (PAH) with a specific focus on its influence on the renin-angiotensin system (RAS). We assessed right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (mPAP), medial pulmonary artery wall thickening, right ventricular (RV) hypertrophy, systolic pulmonary artery pressure (SPAP), pulmonary artery effective elastance (PAEa), RV diastolic pressure (RVDP), RV developed pressure (RVDevP), right ventricular-pulmonary arterial coupling index (RVPAC), RV dp/dt max and dp/dt min. Levels of angiotensin II, angiotensin (1-7), angiotensin-converting enzyme 2 (ACE2), <i>Bmpr2</i>, <i>Smad5</i> and nitrite (NO₂^-) and nitrate (NO₃^-) in the lung and RV were evaluated. The expression of AT1R, MAS receptors, and ACE2 in lung tissue was assessed. FF prevented the increase in RVSP, mPAP, RV hypertrophy, reduced pulmonary arterioles remodeling, and attenuated the rise in SPAP, mPAP, and PAEa. In the RV, it reduced RVDevP and prevented the decrease in dp/dt min, without affecting RVDP. RVPAC showed partial improvement. In lung tissue, FF decreased angiotensin II levels, the Ang II/Ang-(1-7) ratio, and reduced angiotensin II receptor type 1 (AT1R) expression, while preserving the receptor for the angiotensin-(1-7) (MAS) and ACE2. FF tended to restore <i>Bmpr2</i>/<i>Smad5</i> expression. NO₂^- levels were preserved and tended to preserve (NO₃^-) levels. In the RV, Ang-(1-7) increased, ACE2 was preserved, and NO₂^- and NO₃ levels were maintained. FF exerts protective effects in Su/Hx-induced PAH.