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Abstract
Pulmonary artery smooth muscle cells (PASMCs) undergo proliferation by the mammalian target of rapamycin (mTOR) signaling pathway under hypoxia. Hypoxia induces expression of a specific set of microRNAs (miRNAs) in a variety of cell types. We integrated genomic analyses of both small non-coding RNA and coding transcripts using next-generation sequencing (NGS)-based RNA sequencing with the molecular mechanism of the mTOR signaling pathway in hypoxic PASMCs. These analyses revealed hypoxia-induced miR-92b-3p as a potent regulator of the mTOR signaling pathway. We demonstrated that miR-92b-3p directly targets the 3′-UTR of a negative regulator in the mTOR signaling pathway, TSC1. mTOR signaling and consequent cell proliferation were promoted by enforced expression of miR-92b-3p but inhibited by knocking down endogenous miR-92b-3p. Furthermore, inhibition of miR-92b-3p attenuated hypoxia-induced proliferation of vascular smooth muscle cells (VSMCs). Therefore, this study elucidates a novel role of miR-92b-3p as a hypoxamir in the regulation of the mTOR signaling pathway and the pathological VSMC proliferative response under hypoxia. These findings will help us better understand the miRNA-mediated molecular mechanism of the proliferative response of hypoxic VSMCs through the mTOR signaling pathway.
Highlights
Hypoxia contributes to the pathogenesis of various human diseases, including cancer, stroke and pulmonary artery hypertension [1, 2]
MTOR is a well-conserved serine/threonine kinase that plays a central role in the signaling network controlling cell proliferation, growth, survival and metabolism in response to various environmental cues [6]. mammalian target of rapamycin (mTOR) belongs to the phosphoinositide 3-kinase (PI3K)-related kinase family and interacts with several proteins to form two distinct complexes named mTOR complex 1 and 2. mTORC1 regulates cell growth through S6K1 and 4E-BP1 in response to nutrients and growth factors
A heterodimer consisting of tuberous sclerosis 1 (TSC1) and TSC2 is a key upstream regulator of mTORC1 and functions as a GTPase-activating protein (GAP) for the Ras homolog enriched in brain (RHEB) GTPase
Summary
Hypoxia contributes to the pathogenesis of various human diseases, including cancer, stroke and pulmonary artery hypertension [1, 2]. Hypoxia stimulates abnormal proliferation and migration of vascular smooth muscle cells (VSMCs), resulting in decreased luminal diameter and obstruction of pulmonary arteries [3]. The molecular mechanisms involved in the proliferative and migratory responses are still not completely understood, it has been shown that chronic hypoxia-induced proliferation requires activation of the mTOR signaling pathway [4]. MTORC1 regulates cell growth through S6K1 and 4E-BP1 in response to nutrients and growth factors. A heterodimer consisting of tuberous sclerosis 1 (TSC1) and TSC2 is a key upstream regulator of mTORC1 and functions as a GTPase-activating protein (GAP) for the Ras homolog enriched in brain (RHEB) GTPase. GTP-bound RHEB interacts with mTORC1 and activates the mTOR signaling pathway. As a RHEB GAP, TSC1/2 negatively regulates the mTOR signaling pathway
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