© The Author(s) 2020

T. Nakanishi et al. (eds.)Molecular Mechanism of Congenital Heart Disease and Pulmonary Hypertensionhttps://doi.org/10.1007/978-981-15-1185-1_13

13. Ca²⁺ Signal Through Inositol Trisphosphate Receptors for Cardiovascular Development and Pathophysiology of Pulmonary Arterial Hypertension

Akimichi Shibata¹, Keiko Uchida¹  , Katsuhiko Mikoshiba² and Hiroyuki Yamagishi³  

(1)

Department of Pediatrics, Keio University School of Medicine, Shinjuku, Tokyo, Japan

(2)

SIAIS (Shanghai Institute for Advanced Immunochemical Studies), ShanghaiTech University, Shanghai, China

(3)

Division of Pediatric Cardiology, Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan

 

 

Keiko Uchida (Corresponding author)

Email: keiuchid@keio.jp

 

Hiroyuki Yamagishi (Corresponding author)

Email: hyamag@keio.jp

Keywords

Inositol trisphosphate receptorCalcium signalingCardiovascular systemPulmonary arterial hypertension

Inositol triphosphate receptor (IP₃R) is an intracellular Ca²⁺ release channel located on the membrane of the sarco/endoplasmic reticulum (SR/ER), a major intracellular storage site for Ca²⁺. There are three subtypes of IP₃R (IP₃R1, 2, and 3), each of which is known to have versatile roles in the pathophysiology of many organs [1].

In the cardiovascular system, all subtypes of IP₃Rs are expressed from embryonic to postnatal periods. We previously reported that IP₃R1-IP₃R2 or IP₃R1-IP₃R3 double-knockout (DKO) mice died around embryonic day (E) 11.5 due to disorder of cardiovascular development (Fig. 13.1). IP₃R1-IP₃R2 DKO mice showed developmental defects of the myocardium and endocardial cushion, resulting from the disturbance of calcineurin/NFAT signaling [2]. IP₃R1-IP₃R3 DKO mice demonstrated hypoplasia of the outflow tract and the right ventricle of embryonic heart with reduced expression levels of molecular markers for the second heart field [3]. In addition, IP₃R1-IP₃R3 DKO embryos exhibited defects in the vasculature of the labyrinth layers of the placenta, allantois, and yolk sac. Therefore, this suggests the essential redundant roles of endothelial IP₃R1 and 3 for angiogenesis during embryonic and extra-embryonic vascular development [4].

Fig. 13.1

The role of IP₃Rs for cardiogenesis, extra-embryonic vascularization, and suppression of pulmonary arterial hypertension. RV right ventricle, OFT outflow tract, PA pulmonary artery

Recently, we found the specific expression of IP₃R in the pulmonary artery smooth muscle cells (PASMCs) of murine lungs. Although there are some reports that implicated IP₃R1 in vasoconstriction or remodeling in vascular smooth muscle cells [5], the precise role of IP₃Rs in PASMCs remains unknown. Since intracellular Ca²⁺ signaling in PASMCs is a major regulator for pulmonary vasoconstriction and remodeling, its dysregulation leads to the progression of pulmonary arterial hypertension (PAH). It was reported that store-operated Ca²⁺ (SOC) entry was upregulated in PASMCs with PAH patients. Our results suggest that intracellular Ca²⁺ depletion through Ca²⁺ release by IP₃R from the SR/ER may lead to the opening of SOC channels, a mechanism potentially involved in the pathophysiology of PAH (Fig. 13.1) [6].

Acknowledgment

This work was supported by Acterion Academia Prize 2015 to A.S. and JSPS KAKENHI Grant Numbers JP19390288 to H.Y. and JP26461619 to K.U.

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