Perk heterozygosity ameliorates chronic hypoxia-induced pulmonary hypertension and right ventricular hypertrophy in male rats

ABSTRACT

Background

Pulmonary hypertension (PH) is a rare and deadly disease characterized by remodeling of the pulmonary vasculature and increased pulmonary artery pressure. hypobaric pulmonary hypertension (HPH) is clinically classified as group 4 of pulmonary hypertension and has a poor prognosis . Previous reports showed that HPH was associated with increased endoplasmic reticulum (ER) stress. The protein kinase R-like endoplasmic reticulum kinase (PERK) is an ER-associated stress protein. However, to date, its physiological effects on HPH and RVF development remains unknown. This study aimed to assess PERK’s role in HPH and RV function using in vivo experimental model.

Methods

Perk-knockout male Sprague–Dawley rats were generated and were housed in either a hypobaric chamber or in a normoxic environment. After stimulation for 4 weeks, the hemodynamic parameters of the rats were measured. The heart and lungs were harvested for pathological observation. Blood was collected for the detection of inflammatory indexes. The right ventricle tissue was collected to assess phosphorylated-AKT, ROCK1, ET1, and MMP2 protein expression.

Results: we firstly generated Perk+/− rats,

Under normal conditions, Perk^+/− rats showed no changes in mPAP(mean pulmonary artery pressure), RVHI(Right ventricular hypertrophy index), cardiomyocyte size and interstitial fibrosis, and pulmonary vascular remodeling. However, in response to chronic hypoxia, Perk^+/− rats exhibited decreased in mPAP, RVHI, ventricular fibrosis, and lung remodeling compared to wild-type rats. Perk^+/− rats also showed lower expression of phosphor-AKT, ROCK1, ET1, and MMP2 protein in response to chronic hypoxia.

Conclusions

These findings suggest that Perk heterozygosity protects against HPH and Perk may be a suitable target for treating HPH.

KEYWORDS:

• Chronic hypoxic hypoxia
• endoplasmic reticulum stress
• -Perk
• pulmonary hypertension
• right ventricular hypertrophy

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by the National Key Technologies R&D Program for New Drug of China (No.2018ZX09J18109-004);The National Defense Science and Technology Project [20-163-12-ZD-037-002-07];The National Natural Science Foundation of China [No. 82101966];