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Pathogenic Roles of STIM2 and Orai2 in the Development of Pulmonary Arterial Hypertension

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posted on 28.10.2014 by Ruby A. Fernandez
Pulmonary hypertension (PH) is a progressive disease which, if left untreated, will eventually lead to right heart failure and death. Elevated pulmonary arterial pressure (PAP) in patients with PH is mainly caused by an increase in pulmonary vascular resistance (PVR). Sustained vasoconstriction and excessive pulmonary vascular remodeling are two of the major causes for elevated PVR in patients with PH. Excessive pulmonary vascular remodeling is mediated by increased proliferation of pulmonary arterial smooth muscle cells (PASMC) due to PASMC dedifferentiation from a contractile or quiescent to a proliferative or synthetic phenotype. Increased cytosolic Ca2+ concentration ([Ca2+]cyt) in PASMC is a key stimulus for cell proliferation and this phenotypic transition. Voltage dependent Ca2+ entry (VDCE) and store-operated Ca2+ entry (SOCE) are important mechanisms for controlling [Ca2+]cyt. Stromal interacting molecule proteins (e.g., STIM2) and Orai2 both contribute to SOCE and we have previously shown that STIM2 and Orai2, specifically, are upregulated in PASMC from idiopathic pulmonary arterial hypertension (IPAH) patients and from animals with experimental pulmonary hypertension in comparison to normal controls. Our data show that STIM2 and Orai2 are upregulated in proliferating PASMC compared with contractile phenotype of PASMC. Additionally, a switch in Ca2+ regulation is observed in correlation with a phenotype transition from contractile PASMC to proliferative PASMC. PASMC in a contractile state have increased VDCE, while in the proliferative state they have increased SOCE. The data from this study indicate that upregulation of STIM2 and Orai2 is involved in the phenotypic transition of PASMC from a contractile state to a proliferative state; the enhanced SOCE due to upregulation of STIM2 and Orai2 plays an important role in PASMC proliferation.

History

Advisor

Mehta, Dolly

Department

Pharmacology

Degree Grantor

University of Illinois at Chicago

Degree Level

Doctoral

Committee Member

Yuan, Jason Komarova, Yulia Makino, Ayako Machado, Roberto

Submitted date

2014-08

Language

en

Issue date

28/10/2014

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