Abstract / Summary
Background: Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling driven by excessive cellular proliferation and inflammation. Targeting both vasoconstriction and vascular remodeling represents a key therapeutic strategy. Alpha-lipoic acid (α-LA), a metabolic and anti-inflammatory modulator, is associated with modulation of AMPK/mTOR/NF-κB signaling, whereas ambrisentan (AMB) is an endothelin receptor antagonist with established vasodilatory effects. We investigated the beneficial effects of α-LA and AMB, administered alone or in combination, in a monocrotaline (MCT)-induced PAH rat model. Methods: Male rats were randomly assigned to control, MCT, α-LA, AMB, and α-LA + AMB groups. PAH was induced by a single subcutaneous injection of monocrotaline (60 mg/kg). Treatments were administered between days 22 and 35. Echocardiographic measurements were obtained, and histopathological, immunohistochemical, and biochemical analyses were performed in lung and cardiac tissues and in serum. Sample sizes analyzed per outcome were: echocardiography (Control: n = 10, MCT: n = 10, α-LA: n = 8, AMB: n = 9, α-LA + AMB: n = 10), histology (n = 10/group), RVSP (Control: n = 7, MCT: n = 8, α-LA: n = 8, AMB: n = 7, α-LA + AMB: n = 9), Fulton index (Control: n = 10, MCT: n = 10, α-LA: n = 12, AMB: n = 9, α-LA + AMB: n = 10), and ELISA (n = 8/group). Statistical analyses were performed using a web-based statistical software, applying one-way ANOVA or the Kruskal–Wallis test according to data distribution. Results were considered statistically significant at p < 0.05. Results: MCT administration caused pulmonary hypertension and right ventricular remodeling, evidenced by increased RVSP, Fulton index, medial wall thickness, cardiomyocyte diameter, PCNA, α-SMA, p-mTOR, and NF-κB, together with reduced PAT, TAPSE, kallistatin, and p-AMPK levels. α-LA and AMB monotherapy improved right ventricular function and inflammation. Combination therapy produced hemodynamic and structural improvements relative to MCT that were generally comparable to, rather than significantly greater than, either monotherapy, and showed attenuated antiproliferative effects, with higher cardiomyocyte diameter and PCNA levels than either monotherapy alone. All treatments suppressed mTOR activation and the NF-κB increase, accompanied by increased serum kallistatin levels, whereas a significant increase in p-AMPK relative to MCT was observed only with AMB monotherapy. Conclusions: These findings demonstrate that α-LA exerts antiproliferative, anti-remodeling, and anti-inflammatory effects in experimental PAH, suggesting that the AMPK/mTOR/NF-κB signaling pathway and kallistatin may be potential therapeutic targets in pulmonary vascular disease.