Luteolin Ameliorates Experimental Pulmonary Arterial Hypertension via Suppressing Hippo-YAP/PI3K/AKT Signaling Pathway

Abstract

Luteolin is a flavonoid compound with a variety of pharmacological effects. In this study, we explored the effects of luteolin on monocrotaline (MCT) induced rat pulmonary arterial hypertension (PAH) and underlying mechanisms. A rat PAH model was generated through MCT injection. In this model, luteolin improved pulmonary vascular remodeling and right ventricular hypertrophy, meanwhile, luteolin could inhibit the proliferation and migration of pulmonary artery smooth muscle cells induced by platelet-derived growth factor-BB (PDGF-BB) in a dose-dependent manner. Moreover, our results showed that luteolin could downregulate the expression of LATS1 and YAP, decrease YAP nuclear localization, reduce the expression of PI3K, and thereby restrain the phosphorylation of AKT induced by PDGF-BB. In conclusion, luteolin ameliorated experimental PAH, which was at least partly mediated through suppressing HIPPO-YAP/PI3K/AKT signaling pathway. Therefore, luteolin might become a promising candidate for treatment of PAH.

Hippo signaling pathway and respiratory diseases

“…Pathogenesis of PAH is associated with pulmonary artery cell proliferation, vascular remodeling, increased anti-apoptosis, and orthotopic thrombosis [ 78 , 79 ]. Vascular remodeling caused by abnormal proliferation and impaired apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) plays a key role in PAH [ 78 , 80 ]. Increasing studies suggest that YAP of the hippo signaling pathway is involved in pulmonary vascular remodeling [ 78 , 80 ].…”

“…Vascular remodeling caused by abnormal proliferation and impaired apoptosis of pulmonary arterial vascular smooth muscle cells (PAVSMCs) plays a key role in PAH [ 78 , 80 ]. Increasing studies suggest that YAP of the hippo signaling pathway is involved in pulmonary vascular remodeling [ 78 , 80 ]. The inactivation of LATS1 enhances the activity of YAP, which results in the proliferation of PAVSMCs and pulmonary vascular remodeling [ 78 , 80 ].…”

“…Increasing studies suggest that YAP of the hippo signaling pathway is involved in pulmonary vascular remodeling [ 78 , 80 ]. The inactivation of LATS1 enhances the activity of YAP, which results in the proliferation of PAVSMCs and pulmonary vascular remodeling [ 78 , 80 ]. In addition, YAP directly promotes the transcription of Pik3cb which encodes the catalytic subunit P110β of PI3K and enhances TEAD, thereby activating the PI3K/AKT pathway, and then the activation of PI3K/AKT pathway inhibits AKT phosphorylation to improve PAVSMCs proliferation and weaken pulmonary vascular remodeling [ 78 ].…”

“…The inactivation of LATS1 enhances the activity of YAP, which results in the proliferation of PAVSMCs and pulmonary vascular remodeling [ 78 , 80 ]. In addition, YAP directly promotes the transcription of Pik3cb which encodes the catalytic subunit P110β of PI3K and enhances TEAD, thereby activating the PI3K/AKT pathway, and then the activation of PI3K/AKT pathway inhibits AKT phosphorylation to improve PAVSMCs proliferation and weaken pulmonary vascular remodeling [ 78 ]. Moreover, inactivation of LATS1 is caused by negative bidirectional cross-linking between YAP-fibronectin and integrin-linked kinase 1 (ILK1), and the dysregulation of LATS1-YAP promotes the production of fibronectin and activates ILK1 in PAVSMCs [ 80 , 81 ].…”

Guanxin V Acts as an Antioxidant in Ventricular Remodeling

“…Luteolin, a widely distributed flavonoid found in many herbal extracts ( 12 ), is known to be a potent antioxidant and is demonstrated to have protective actions against Ang II-induced VR, which could be mediated through attenuation of oxidative stress ( 40 ). Meanwhile, luteolin improved monocrotaline-induced right VR at least partly through suppressing HIPPO-YAP/PI3K/AKT signaling pathway ( 41 ). Tanshinone IIA may alleviate VR in rats by reducing oxidative stress, inflammatory response, and cardiomyocyte apoptosis ( 42 , 43 ), and enhanced autophagy ( 44 ) via the inhibition of TLR4/MyD88/NF-κB signaling pathway ( 45 ) and activation of SIRT1 signaling pathway ( 43 ).…”