Abstract
Over the last years, small non-coding microRNAs (miRNAs) have emerged as central actors of PAH etiology. Strong miRNA expression disorders occur in lungs as well as in right ventricle (RV) of PAH patients, which respectively lead to vascular remodeling of the distal pulmonary arteries and to RV failure. On the other hand, our understanding of PAH physiopathology has recently increased with the implication of DNA damage and DNA damage response (DDR) in this disease. Interestingly, DDR was described as a regulator of miRNA processing in both healthy and pathological conditions. In this review, we will first summarize miRNA expression impaired in lung and RV of PAH patients, then we will provide evidence that DDR could be at origin of miRNA pathway defects observed in pulmonary hypertension.
Highlights
Pulmonary arterial hypertension (PAH) is a lethal vasculopathy clinically defined by a mean pulmonary arterial pressure over 25 mmHg at rest
Strong miRNA expression disorders occur in lungs as well as in right ventricle (RV) of PAH patients, which respectively lead to vascular remodeling of the distal pulmonary arteries and to RV failure
We will first summarize miRNA expression impaired in lung and RV of PAH patients, we will provide evidence that DNA damage response (DDR) could be at the origin of miRNA pathway defects observed in pulmonary hypertension
Summary
Pulmonary arterial hypertension (PAH) is a lethal vasculopathy clinically defined by a mean pulmonary arterial pressure over 25 mmHg at rest. It is well established that alteration of Bcl-2 expression plays a key role in the PAH pulmonary artery remodeling and is closely linked to impairment in miRNA expression [44] This pro-apoptotic protein is targeted by multiple miRNA such as miR-21 and by miR-155 [45], which decreases apoptosis by inhibiting FOXO3a, a protein associated with extensive vascular growth [46,47,48,49,50]. As observed for p53, Myc is targeted by other miRNAs implicated in PAH pathophysiology such as miR143/145 [131], miR-34 [132], miR-451 [133], and indirectly by miR-210 through MNT [134] as described in cancer, resulting in impairment of Myc function This tight and reciprocal regulation of miRNA by DDR mechanisms was already well described in cancer, which highlights the complexity of these relationships in pathological processes. Crosstalk between miRNAs and DDR mechanisms is one step ahead in the understanding of PAH etiology, but still remains far from being fully understood
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