Abstract
Multiple causes are associated with the complex mechanism of pathogenesis of pulmonary arterial hypertension (PAH), but the molecular pathway in the pathogenesis of PAH is still insufficiently understood. In this study, we investigated epigenetic changes that cause PAH induced by exposure to combined Th2 antigen (Ovalbumin, OVA) and urban particulate matter (PM) in mice. To address that, we focused on the epigenetic mechanism, linked to microRNA (miR)-135a. We found that miR-135a levels were significantly increased, and levels of bone morphogenetic protein receptor type II (BMPR2) which is the target of miR-135a, were significantly decreased in this experimental PAH mouse model. Therefore to evaluate the role of miR-135a, we injected AntagomiR-135a into this mouse model. AntagomiR-135a injected mice showed decreased right ventricular systolic pressures (RVSPs), right ventricular hypertrophy (RVH), and the percentage of severely thickened pulmonary arteries compared to control scrambled miRNA injected mice. Both mRNA and protein expression of BMPR2 were recovered in the AntagomiR-135a injected mice compared to control mice. Our study understands if miR-135a could serve as a biomarker helping to manage PAH. The blocking of miR-135a could lead to new therapeutic modalities to alleviate exacerbation of PAH caused by exposure to Th2 antigen and urban air pollution.
Highlights
Pulmonary hypertension (PH) is a rare disease that is defined in patients based on a mean pulmonary arterial pressure of more than or equal to 25 mmHg [1, 2]
pulmonary arterial hypertension (PAH) is characterized by severe pulmonary arterial remodeling with smooth muscle cell proliferation, which results in right ventricular hypertrophy (RVH), increased right ventricular systolic pressures (RVSP), and right heart failure and death [4,5,6]
RVSPs and bone morphogenetic protein receptor type II (BMPR2) expression are inversely correlated among mice exposed to PBS and mice exposed to OVA & particulate matter (PM) (Figure 1A)
Summary
Pulmonary hypertension (PH) is a rare disease that is defined in patients based on a mean pulmonary arterial pressure of more than or equal to 25 mmHg [1, 2]. The pathogenesis of PH is complex, and multiple factors can lead to different types of PH. One of those types, pulmonary arterial hypertension (PAH), which is a Group 1 PH, is caused by defects in primary arteries of the lung. Urban particulate matter (PM) exacerbates pulmonary arterial remodeling and increased RVSPs induced by prolonged exposure to a T helper type 2 (Th2) antigen (Ovalbumin, OVA) [7]. We demonstrated that neutralization of IL-13 and IL-17A prevent the development of PAH [8], the downstream molecular mechanisms are unclear. To further understand PAH development, we examined the epigenetic mechanisms by which exposure to Th2 antigen and urban PM exacerbates the PAH phenotype. To evaluate a specific molecular mechanism, we focused on miR-135a
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