Korean J Physiol Pharmacol.  2013 Feb;17(1):1-8. 10.4196/kjpp.2013.17.1.1.

Regulation of Ca2+ Signaling in Pulmonary Hypertension

• Firth AL
• Won JY
• Park WS

• KMID: 1432756
• DOI: http://doi.org/10.4196/kjpp.2013.17.1.1

Abstract

Understanding the cellular and molecular mechanisms involved in the development and progression of pulmonary hypertension (PH) remains imperative if we are to successfully improve the quality of life and life span of patients with the disease. A whole plethora of mechanisms are associated with the development and progression of PH. Such complexity makes it difficult to isolate one particular pathway to target clinically. Changes in intracellular free calcium concentration, the most common intracellular second messenger, can have significant impact in defining the pathogenic mechanisms leading to its development and persistence. Signaling pathways leading to the elevation of [Ca2+]cyt contribute to pulmonary vasoconstriction, excessive proliferation of smooth muscle cells and ultimately pulmonary vascular remodeling. This current review serves to summarize the some of the most recent advances in the regulation of calcium during pulmonary hypertension.

Keyword

CaSR; NFAT; ORAI; STIM; TRP

MeSH Terms

Calcium
Humans
Hydrogen-Ion Concentration
Hypertension, Pulmonary
Myocytes, Smooth Muscle
Quality of Life
Second Messenger Systems
Vasoconstriction
Calcium

Figure

• 

  Fig. 1 The calcineurin-NFAT pathway as an integrator of multiple signaling pathways in the pathogenesis of pulmonary hypertension (PH). NFAT resides in the cytoplasm of resting cells in a phosphorylated and inactive state. Endothelial dysfunction occurs early in PH and results in an increased release of vasoconstrictors (Endothelin-1 [ET-1] and 5-Hydroxytryptamine [5-HT]) and decreased vasodilators (Prostaglandin [PGI2] and nitric oxide synthase [NOS]). These vasoconstrictors can stimulate phospholipase C (PLC) coupled cell surface receptors leading to mobilization of calcium ions (Ca2+) from intracellular stores via inositol trisphosphate (IP3). The elevated intracellular calcium ([Ca2+]i) can cause further Ca2+ influx via Ca2+ release-activated Ca2+ channels (CRAC). Addtionally, the down-regulation of Kv1.5 depolarized PASMC and will lead to the influx of via L-type voltage dependent Ca2+ channels (VDCC). The elevated [Ca2+]i activates phosphatase calcineurin which dephosphorylates NFAT allowing for its translocation to the nucleus. Here it is involved in the regulation of multiple genes. Multiple NFAT binding elements are present in the promoter regions of both the Kv1.5 and bcl-2 genes leading to a promotion of cell proliferation and suppressing mitochondrial-dependent apoptosis. Cyclosporin A inhibits calcineurin-ubstrate interactions and VIVITs electively inhibits NFAT activation.

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