New Insights Into Hypoxia-induced Pulmonary Hypertension Reveal Key Signaling Pathways
A new study entitled “mTORC1 Is Involved in Hypoxia-Induced Pulmonary Hypertension Through the Activation of Notch3” published in Journal of Cellular Physiology reports that both mTORC1 and Notch3 signaling pathways are associated with Hypoxia-Induced Pulmonary Hypertension.
In hypoxic pulmonary hypertension (HPH), one of the most common forms of pulmonary hypertension, low oxygen levels induce pulmonary arteries’ vasoconstriction so that increasing blood flow cannot reach already damaged lung areas by lack of oxygen. Therefore, HPH leads to increased pulmonary arterial pressure and right ventricular hypertrophy.
In lung tissues isolated from PH patients, increased levels of mTOR was observed. mTOR is a serine/threonine protein kinase with two complexes, mTORC1 and mTORC2, that is well-conserved and regulates key cellular processes such as cell growth, cell-cycle progression, proliferation, and autophagy. More specifically, mTORC1 and mTORC2 were reported as required to pulmonary vascular proliferation and remodeling in idiopathic pulmonary arterial hypertension (IPAH) patients and rat hypoxia model of PH. Another pathway recently identified in HPH was the Notch3 pathway (with Notch being a conserved pathway that regulates cell differentiation and development). Mice without Notch 3 – “knock-out” mice — failed to develop wall thickening in the pulmonary arteries and high right ventricular systolic pressures (RVSP) during hypoxia.
Therefore, in this study, the authors aimed to understand if these two pathways had an interdependent role in HPH. The authors found that mTORC1 hyperactivation in HPH was partially dependent activation of Notch3. Inducing progressive HPH in mice was accompanied by activation of mTORC1 and Notch3 in lung tissue and pulmonary arterioles. Additionally, pretreating mice with the inhibitor of mTORC1 — rapamycin — improved both pulmonary arterial pressure and remodeling but also suppressed mTORC1 and Notch3 activation by hypoxia. Mice treated with a Notch inhibitor improved hypoxia-induced PH. The findings in mice were further confirmed by in viro studies with human pulmonary arterial smooth muscle cell (PASMC) treated with oxygen at 3%. Notch3 overexpression in these cells impaired the rapamycin inhibitory effect oh cells’ proliferation.
The authors’ findings thus suggest that both pathways — mTROC1 and Notch3 – and that the mTORC hyperactivation depends partially on Notch 3 signaling pathway.