Novel Pyrazolo[3,4-b] Pyridine Derivative (HLQ2g) Attenuates Hypoxic Pulmonary Hypertension via Restoring cGKI Expression and BMP Signaling Pathway.

Lijun Li,Xiaohui Li,Ying Li,Xiaoting Tian,Liqing Hu,Minghui Yin,Qianbin Li,Xiangrong He,Congke Zhao

doi:10.3389/fphar.2021.691405

Abstract

Pulmonary hypertension (PH) is an extremely serious cardiopulmonary disease, finally leading to progressive right ventricular failure and death. Our previous studies have nominated HLQ2g, a pyrazolo[3,4-b] pyridine derivative stimulating soluble guanylate cyclase (sGC), as a new candidate for the treatment of PH, but the specific mechanism is still not clear. The PH model induced by hypoxia was established in rats. Right ventricular systolic pressure (RVSP) was assessed by jugular vein catheterization. RV weight was the index to evaluate RV hypertrophy. The protein levels of cGMP-dependent protein kinase type I (cGKI), bone morphogenetic protein receptor 2 (BMPR2), phosphorylated Smad1/5/8 (p-Smad1/5/8), and inhibitor of differention 1 (Id1) in pulmonary artery and human pulmonary artery smooth muscle cells (HPASMCs) were determined by western blotting. Cell proliferation and migration were evaluated. In the whole experiment, the first clinically available sGC stimulator Riociguat was used as the reference. In hypoxic PH rat model, elevated RVSP and RV hypertrophy were significantly reduced by HLQ2g treatment. Both Riociguat and HLQ2g attenuated vascular remodeling accompanied with up-regulated cGKI expression and BMP signaling pathway, which was characterized by elevated expression of BMPR2, p-Smad1/5/8, and Id1 in HPH rats. In addition, HLQ2g inhibited proliferation and migration of HPASMCs induced by hypoxia and platelet-derived growth factor (PDGF), restored BMPR2 signaling, which was recalled by Rp-8-Br-PET-cGMPS, the inhibitor of cGKI. In summary, the novel pyrazolo[3,4-b] pyridine derivative HLQ2g can alleviate HPH progression by up-regulating cGKI protein and BMP signaling pathway.

Highlights

Pulmonary hypertension (PH) refers to the resting mean pulmonary arterial pressure ≥20 mmHg as evaluated by right heart catheterization, which has always been an important clinical challenge due to its high mortality (Simonneau et al, 2019)
Pharmacological stimulation of soluble guanylate cyclase (sGC) have intracellular effects by augmenting the formation of cyclic guanosine monophosphate (cGMP) that can be degraded by phosphodiesterase 5 (PDE-5)
The presence or absence of ODQ had no significant difference on the levels of cGMP (Figure 1C). This is mainly due to the rapid cGMP degradation catalyzed by the intracellular PDE-5

Summary

Introduction

Pulmonary hypertension (PH) refers to the resting mean pulmonary arterial pressure ≥20 mmHg as evaluated by right heart catheterization, which has always been an important clinical challenge due to its high mortality (Simonneau et al, 2019). Continuous elevation of pulmonary artery pressure increases right ventricular (RV) afterload, which may lead to right heart failure or even death if left untreated (McLaughlin et al, 2009). Nitric oxide (NO) has been revealed as critical messenger molecule in PH for long history and currently commonly used clinical drugs including Sildenafil, Tadalafil, and Riociguat exhibit therapeutical effects mainly by targeting on NO pathway. Experimental studies have demonstrated that sGC stimulator bear considerable potential benefits, including preventing or even reversing left ventricular hypertrophy and fibrosis, and reducing ventricular afterload through systemic and pulmonary vasodilation (Armstrong et al, 2018). Similar to Riociguat, HLQ2g can regulate sGC/ cGMP signaling pathway in PH model (Hu et al, 2020), but the specific mechanism of HLQ2g in the PH treatment remains to be elucidated

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