The Isoquinoline-Sulfonamide Compound H-1337 Attenuates SU5416/Hypoxia-Induced Pulmonary Arterial Hypertension in Rats

Abstract

Pulmonary arterial hypertension (PAH) is characterized by elevated pulmonary arterial pressure and right heart failure. Selective pulmonary vasodilators have improved the prognosis of PAH; however, they are not able to reverse pulmonary vascular remodeling. Therefore, a search for new treatment agents is required. H-1337 is an isoquinoline-sulfonamide compound that inhibits multiple serine/threonine kinases, including Rho-associated protein kinase (ROCK) and mammalian target of rapamycin (mTOR). Here, we investigated the effects of H-1337 on pulmonary hypertension and remodeling in the pulmonary vasculature and right ventricle in experimental PAH induced by SU5416 and hypoxia exposure. H-1337 and H-1337M1 exerted inhibitory effects on ROCK and Akt. H-1337 inhibited the phosphorylation of myosin light chain and mTOR and suppressed the proliferation of smooth muscle cells in vitro. H-1337 treatment also suppressed the phosphorylation of myosin light chain and mTOR in the pulmonary vasculature and decreased right ventricular systolic pressure and the extent of occlusive pulmonary vascular lesions. Furthermore, H-1337 suppressed aggravation of right ventricle hypertrophy. In conclusion, our data demonstrated that inhibition of ROCK and mTOR pathways with H-1337 suppressed the progression of pulmonary vascular remodeling, pulmonary hypertension, and right ventricular remodeling.

Cavin-2 loss exacerbates hypoxia-induced pulmonary hypertension with excessive eNOS phosphorylation and protein nitration

“…However, we were able to show that PKG, which is essential for the vasorelaxation mechanism, may be impaired by Cavin-2 loss-mediated nitration, leading to accelerate MLC phosphorylation. Previous papers reporting the relationship between PH and MLC phosphorylation evaluated PASMCs isolated from PH lungs [ 25 , 27 , 28 ], which differ from the experiments in our method. Additionally, the hypoxia-induced PH model is reversible, using it as a suitable model for the study of early PH [ 29 , 30 ].…”

Weighted gene co-expression network analysis reveals the hub genes associated with pulmonary hypertension

“…33 Inhibition of mTOR phosphorylation reduces pulmonary artery smooth muscle cell proliferation. 34 PSMD2, also known as 26S proteasome, is involved in the cell cycle, apoptosis, repair of DNA damage, and maintenance of protein homeostasis. 35 PSMD2 regulates cell proliferation and participates in cell cycle progression in breast cancer 36 and hepatocellular carcinoma.…”