An article published in Experimental Biology and Medicine identifies a new signaling pathway that promotes heart failure in pulmonary hypertension. The study, led by Dr. Matthias Brock, from the Division of Pulmonology, University Hospital of Zurich, University of Zurich in Switzerland, reports that inhibition of MALAT1, a long noncoding RNA, reduces heart hypertrophy in mice with pulmonary hypertension.
Pulmonary hypertension (PH) is a chronic increase in blood pressure within the arteries, veins or capillaries of the lungs that results in shortness of breath, dizziness, fainting, leg swelling and other symptoms. If left untreated, PH can lead to heart failure. PH can be attributed to many different clinical and pathophysiological conditions. But, the common final event is remodeling of the pulmonary vessels. This remodeling is due to abnormal proliferation, death and migration of endothelial cells as well as vascular smooth muscle cells. Although tumor-like alterations in smooth muscle and endothelial cells are important events, the signaling pathways responsible for vascular remodeling in PH are not well defined. Delineating these pathways will provide new targets for drug discovery and ultimately new treatments for patients.
Long noncoding RNAs (lncRNAs) are large (<200 nt) RNA molecules that most often do not encode proteins and function by regulating gene expression. MALAT1, or metastasis-associated lung adenocarcinoma transcript 1, is an lncRNA that controls normal vascular smooth muscle cell proliferation and apoptosis. In this study, Dr. Brock and colleagues used cell culture and in vivo model systems to examine the role of MALAT1 in hypoxia-induced PH. Hypoxic conditions increased MALAT1 expression/activity. Conversely, knockdown of MALAT1 inhibited vascular smooth muscle cell migration and proliferation, most likely via alterations in the expression of cyclin dependent kinases. In an in vivo model, MALAT1 expression/activity was associated with right ventricular hemodynamics, and therapeutic intervention directed against MALAT1 ameliorated right heart hypertrophy. Dr. Brock said that this study “provides novel insights in the pathogenesis of pulmonary vascular remodelling and confirms that lncRNAs affect the expression of important cell cycle regulators that favour the pro-proliferative phenotype of vascular smooth muscle cells.”
Targeting of MALAT1 in the mouse model of hypoxia–induced PH
(a) Study design of the in vivo experiments. (b) As evaluated by qPCR, MALAT1 expression was significantly increased in the lungs of hypoxic GapmeR control mice, whereas the treatment with GapmeR MALAT1 significantly reduced the expression of MALAT1. (c) The relative heart weight of each mouse was measured demonstrating that GapmeR control mice developed heart hypertrophy, whereas mice treated with GapmeR MALAT1 had a significantly reduced relative heart weight. (d) The RVP measurement by right heart catheterization (RHC) showed significantly increased RVP in hypoxic control mice indicating the development of PH in these mice. However, the RVP was found to be unchanged between GapmeR control and GapmeR MALAT1 treated mice. Statistical analysis by one-way ANOVA with Tukey post hoc test (b–d) (*P < 0.05, **P < 0.01, ***P < 0.001)
Dr. Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine, said, “Brock and colleagues provide the seminal study of the functional role of MALAT1 in the pulmonary vasculature. They demonstrate that MALAT1 is a potential target for reducing heart hypertrophy during hypoxia induced pulmonary hypertension.”