Idiopathic pulmonary arterial hypertension (IPAH) is a progressive and fatal disease. Sustained pulmonary vasoconstriction and vascular remodeling are the major causes for the elevated PVR and PAP in IPAH patients. An increase in cytosolic Ca ([Ca ]cyt) in pulmonary arterial smooth muscle cells (PASMC) is a major 2+ 2+ trigger for pulmonary vasoconstriction and for pulmonary vascular remodeling due to its stimulatory effect on PASMC proliferation and migration. Abnormally enhanced Ca2+ entry in PASMC because of upregulated expression of membrane receptors (e.g., CaSR) and Ca2+ channels (e.g., TRPC6/C3) contributes to the development and progression of PAH. Downregulation of voltage-gated K+ (Kv) channel expression and decrease in Kv currents (IK(V)) in PASMC contribute to a) increasing PASMC contraction, proliferation and migration by inducing membrane depolarization that opens voltage-dependent Ca2+ channels and raises [Ca ]cyt and b) inhibiting PASMC apoptosis by attenuating apoptotic volume decrease (AVD) and maintaining 2+ high [K ]cyt to inhibit caspases. Enhanced PASMC proliferation and inhibited PASMC apoptosis both contribute + to pulmonary vascular wall thickening. Our data show that selectively increased miRNAs are involved in posttranscriptionally downregulating Kv channels to stimulate PASMC proliferation and inhibit PASMC apoptosis in IPAH patients. Ca2+-sensing receptor (CaSR), a G protein-coupled receptor that can be activated by extracellular Ca2+, is upregulated in IPAH-PASMC compared to normal PASMC. Activation of CaSR in IPAH-PASMC induces receptor-operated Ca entry (ROCE) via diacylglycerol (DAG), while IP3-mediate active 2+ depletion of Ca2+ from the SR results in store-operated Ca2+ entry (SOCE). Extracellular Ca2+-induced CaSR activation also inhibits Kv channels and activate other signal transduction pathways to induce cell proliferation. The overall goal of this research program is to continue to investigate: i) the molecular and cellular mechanisms involved in the posttranscriptional downregulation of Kv channels and other K+ channels by miRNAs that are enhanced in PASMC from IPAH patients; ii) the genetic and molecular mechanisms responsible for the transcriptional upregulation of CaSR and receptor-operated (ROC) and store-operated (SOC) Ca2+ channels (e.g., TRPC3/C6, TRPV1, Orai1/2 and STIM1/2) in PASMC from IPAH patients; iii) the cellular and pathophysiological mechanisms involved in the CaSR-mediated functional activation of TRPC/Orai channels (and STIM1/2 oligomerization and translocation) and functional inhibition of Kv channels in PASMC from IPAH patients; and iv) the potential targets involved in the pathogenic Ca2+ signaling that can be used to develop novel therapy or combination therapy for PAH. Our laboratory has extensive research and technical experience in studying pathogenic mechanisms of IPAH and pulmonary hypertension associated with hypoxic lung disease. The forthcoming results from these studies will provide highly impactful insights into developing novel therapies for IPAH and other forms of pulmonary hypertension.

Public Health Relevance

Idiopathic pulmonary arterial hypertension (IPAH) is a rare and fatal disease that predominantly affects young women. Abnormalities in pulmonary arteries, the blood vessels in the lungs, have been shown to relate to the elevated blood pressure in the lungs. This study is designed to determine the role of receptors and ion channels, proteins on cell membrane that mediate cell growth and mobility in the cellular processes that lead to the high blood pressure in the lungs in patients with this devastating disease, and to reveal potential novel targets for therapeutic approaches to treat IPAH.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Unknown (R35)
Project #
7R35HL135807-04
Application #
9927824
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Xiao, Lei
Project Start
2017-01-15
Project End
2023-12-31
Budget Start
2019-08-09
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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