AMPK and the Challenge of Treating Hypoxic Pulmonary Hypertension

Flores, Karen; Siqués, Patricia; Arribas, Silvia M.

doi:10.3390/ijms23116205

Cited by 17 publications

(4 citation statements)

References 255 publications

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“…AMPK was a critical regulator of various biological processes, including cell growth, proliferation, autophagy and metabolism. Previous studies demonstrated the involvement of AMPK in the abnormal proliferation of PASMCs during PAH development [45,46].…”

Section: Discussionmentioning

confidence: 97%

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates vascular remodeling in MCT-induced pulmonary arterial hypertension

Chen,

Yu,

Lian

et al. 2023

Preprint

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Background Pulmonary arterial hypertension (PAH) is a progressive, devastating vascular disease that eventually leads to right heart failure (RHF). Recent studies have shown that sodium-glucose cotransporter 2 inhibitors (SGLT2is) are effective in reducing cardiovascular events in patients with HF, but their efficacy in treating PAH remains uncertain. The aim of this study was to investigate the effects of canagliflozin (CANA), an SGLT2i with mild SGLT1 inhibitory effects, on rats with PAH, as well as its direct impact on pulmonary arterial smooth muscle cells (PASMCs). Methods PAH was induced in rats by subcutaneous injection of monocrotaline (MCT) (40 mg/kg), followed by 4 weeks of treatment with CANA by gavage (30 mg/kg/day) or saline alone. Echocardiography, hemodynamic measurements, and histological staining were performed to evaluate pulmonary vascular and right ventricular (RV) structure and function. The effect of CANA on cell proliferation was further investigated in PASMCs. Platelet-derived growth factor (PDGF)-BB, AMP kinase (AMPK) inhibitor compound C (CC) and siSGLT1 were utilized to explore the molecular regulation mechanism of CANA. Results Pulmonary artery and RV remodeling and dysfunction in PAH were alleviated with CANA, as assessed by echocardiography. Hemodynamic parameters, such as RV systolic pressure, and structural of pulmonary arteriole, including vascular wall thickness and wall area, were reduced by CANA treatment. RV hypertrophy index, cardiomyocyte hypertrophy, and fibrosis were decreased with CANA treatment. In vitro, PASMCs proliferation was inhibited by CANA, regardless of PDGF-BB stimulation. Activation of AMPK was induced by CANA treatment in cultured PASMCs in a time- and concentration-dependent manner. These effects of CANA were attenuated by treatment with CC. Abundant expression of SGLT1 was observed in PASMCs and pulmonary arteries of rats, while SGLT2 expression was undetectable. SGLT1 was increased in response to PDGF-BB stimulation, while PASMCs proliferation was inhibited and beneficial effects of CANA were counteracted by knockdown of SGLT1. Conclusions It is demonstrated for the first time that CANA inhibited the proliferation of PASMCs by regulating SGLT1/AMPK signaling and thus exerted an anti-proliferative effect on MCT-induced PAH. Our research revealed a novel mechanism for the beneficial effects of CANA on pulmonary vasculature.

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Section: Discussionmentioning

confidence: 97%

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates vascular remodeling in MCT-induced pulmonary arterial hypertension

Chen,

Yu,

Lian

et al. 2023

Preprint

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“…The combination of all drugs strengthens lung qi and warms Yang qi, causing blood stasis to dispel phlegm. Hypoxic pulmonary hypertension (HPH) is a long-term rise in pulmonary artery pressure caused by constriction of blood vessels and vascular reformation of the pulmonary arteries [12]. Pulmonary vascular remodeling is defined by thickening of the pulmonary artery media.…”

Section: Discussionmentioning

confidence: 99%

Qibai Pingfei capsule induces apoptosis of pulmonary artery smooth muscle cells in hypoxic rats by regulating PI3K/AKT/mitochondrial signaling pathway

Tong,

Zhang,

Zhu

et al. 2023

Trop. J. Pharm Res

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Purpose: To investigate the effect of Qibai Pingfei capsules (QBPF) medicated serum on the apoptosis of rat pulmonary artery smooth muscle cells (PASMC) in hypoxic rats, and to determine the relationship between that effect and PI3K/Akt/mitochondrial apoptosis pathway.Methods: Rat PASMCs were isolated, cultured, and the optimal hypoxic time and concentration of QBPF were determined by CCK-8 method. Hypoxic rats were treated with QBPF, QBPF + LY294002, or QBPF + SC79. Apoptosis and mitochondrial membrane potential were assessed using Annexin VFITC/ PI, Hoechst 33258, and Rho123 staining. The protein expression levels of AKT, P-AKT, and apoptosis-related proteins were evaluated via western blot.Results: CCK-8 studies showed that the optimal hypoxic time was 24 h, while the optimal concentration of QBPF was 20 %. Annexin V-FITC/PI double staining and Hoechst 33258 assay revealed that QBPF significantly promoted the apoptosis of PASMCs in hypoxic rats (p < 0.05). Rho123 test results showed that QBPF inhibited mitochondrial membrane potential level in hypoxic rats' PASMCs, which was enhanced by PI3K inhibitor LY29002 and inhibited by AKT agonist SC79 (p < 0.05). Western blot showed that QBPF reduced the protein level of P-AKT and Bcl-2, and raised the protein levels of Bad, Bax, CytC, casepase-9 and casepase-3, which was enhanced by LY29002 and blocked by SC79 (p < 0.05). No major changes in AKT protein expression were seen between the groups.Conclusion: In hypoxic rats, QBPF blocks PI3K/AKT signaling pathway and regulates the activation of downstream Bcl-2 family members, thus activating mitochondrial apoptosis pathway and triggering PASMC death.

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“…The oxidative stress response may damage blood vessels, undermine endovascular homeostasis, increase cellular Ca 2+ concentrations, and result in the degradation of proteins, lipids, and DNA [ 8 , 9 ]. During hypoxia, superoxide anions formed in the body alleviate NO-mediated vasodilation by producing peroxynitrites [ 10 , 11 ]. Thus, treatment of antioxidant stress has potential for the treatment of HAPH.…”

Section: Introductionmentioning

confidence: 99%

Protective effects of the Terminalia bellirica tannin-induced Nrf2/HO-1 signaling pathway in rats with high-altitude pulmonary hypertension

Aimaier

Yang

Lei

et al. 2023

BMC Complement Med Ther

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Background Oxidative stress and endothelial cell dysfunction induced by high-altitude hypoxia have important roles in the pathological process of high-altitude pulmonary hypertension (HAPH). Tannins present in Terminalia bellirica (Gaertn.) Roxb. (TTR) have pharmacological activities that produce oxidation resistance and exert anti-inflammatory effects. Whether TTR exerts a protective effect on HAPH remains unknown. Methods A rat model of HAPH was established. The mean pulmonary arterial pressure (mPAP) of the animals was measured, the serum levels of SOD, MDA, and GSH-Px were measured using ELISA, and the expression of Bax, Bcl-2, Nrf2, and HO-1 proteins in the lung tissue of each group of rats was measured using Western blotting. Pathological changes in the lung tissue were also observed. A model of damage to H2O2-induced pulmonary artery endothelial cells (PAECs) was generated, and cell proliferation was measured using CCK-8 assays. Flow cytometry was used to measure ROS levels in PAECs. Western blotting was used to detect the expression of Bax, Bcl-2, Nrf2, and HO-1 proteins in PAECs. Results The hemodynamic and pathologic findings showed that the mPAP of HAPH rats increased markedly, and the vascular wall thickness increased (P < 0.05). TTR reduced mPAP, alleviated or slowed pulmonary arterial remodeling, increased GSH-Px and SOD activity, lowered the level of MDA (P < 0.05), and downregulated the expression of Bax in the lung tissues of HAPH rats, while the expression of Bcl-2, Nrf2, and HO-1 was upregulated (P < 0.05). The results of the cell experiments showed that TTR inhibited H2O2-induced PAEC apoptosis and ROS production (P < 0.05), downregulated the expression of Bax in PAECs, and upregulated the expression of Bcl-2, Nrf2, and HO-1 (P < 0.05). Conclusion The results suggest that TTR reduces pulmonary arterial pressure, decreases oxidative stress during HAPH, and exerts protective effects in rats with HAPH and that its mechanism of action is related to regulation of the Nrf2/HO-1 signaling pathway.

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AMPK and the Challenge of Treating Hypoxic Pulmonary Hypertension

Cited by 17 publications

References 255 publications

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates vascular remodeling in MCT-induced pulmonary arterial hypertension

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates vascular remodeling in MCT-induced pulmonary arterial hypertension

Qibai Pingfei capsule induces apoptosis of pulmonary artery smooth muscle cells in hypoxic rats by regulating PI3K/AKT/mitochondrial signaling pathway

Protective effects of the Terminalia bellirica tannin-induced Nrf2/HO-1 signaling pathway in rats with high-altitude pulmonary hypertension

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