α-Lipoic Acid, with or Without Ambrisentan, Attenuates Experimental Pulmonary Arterial Hypertension: Associations with AMPK/mTOR/NF-κB Signaling and Kallistatin
5 affiliations
- 1Department of Medical Pharmacology, Faculty of Medicine, İnönü University, Malatya 44280, Türkiye
- 2Department of Medical Pathology, Faculty of Medicine, İnönü University, Malatya 44280, Türkiye
- 3Department of Cardiology, Faculty of Medicine, İnönü University, Malatya 44280, Türkiye
- 4Department of Physiology, Faculty of Medicine, İnönü University, Malatya 44280, Türkiye
- 5Department of Medical Pharmacology, Institute of Health Sciences, İnönü University, Malatya 44280, Türkiye
Abstract
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.
Related
- Intratracheal Administration of Benzbromarone Attenuates Pulmonary Vascular Remodeling and Improves Survival in Rats with Monocrotaline-Induced Pulmonary Hypertension
- Tacrolimus attenuates BCL-2/BAX-mediated chondrocyte apoptosis and cartilage matrix degradation in experimental osteoarthritis
- A plant-based diet attenuates hypertension-induced renal and hepatic stress: an exploratory study
- Spermidine attenuates monocrotaline-induced pulmonary arterial hypertension with HADHA-associated improvements in fatty acid oxidation and mitochondrial redox homeostasis
- Electroacupuncture attenuates high-salt-induced hypertension by modulating neuronal excitability and proteomic signatures in the paraventricular nucleus of mice
BibTeX
@article{ayik2026αlipoic,
title = {{α-Lipoic Acid, with or Without Ambrisentan, Attenuates Experimental Pulmonary Arterial Hypertension: Associations with AMPK/mTOR/NF-κB Signaling and Kallistatin}},
author = {Seyhan Ayik and Mustafa Huz and Zeynep Ulutas and Mehmet Ertugrul Balkar and Kevser Tanbek and Rumeysa Sonmez and Ruveyda Ummugulsum Unal and Eylem Karadag and Seymanur Baydak and Lokman Hekim Tanriverdi and Onural Ozhan},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101432},
url = {https://www.mdpi.com/2218-273X/16/10/1432},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - α-Lipoic Acid, with or Without Ambrisentan, Attenuates Experimental Pulmonary Arterial Hypertension: Associations with AMPK/mTOR/NF-κB Signaling and Kallistatin
AU - Seyhan Ayik
AU - Mustafa Huz
AU - Zeynep Ulutas
AU - Mehmet Ertugrul Balkar
AU - Kevser Tanbek
AU - Rumeysa Sonmez
AU - Ruveyda Ummugulsum Unal
AU - Eylem Karadag
AU - Seymanur Baydak
AU - Lokman Hekim Tanriverdi
AU - Onural Ozhan
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101432
UR - https://www.mdpi.com/2218-273X/16/10/1432
AB - 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.
SN - 2218-273X
ER -