Functional Upregulation of STIM-1/Orai-1-Mediated Store-Operated Ca2+ Contributing to the Hypertension Development Elicited by Chronic EtOH Consumption.
BACKGROUND
Chronic ethanol (EtOH) consumption has been associated with deleterious effects on the cardiovascular system by abnormal calcium (Ca2+) handling. Store-operated Ca2+ entry (SOCE) is related to cardiovascular remodeling which leads to the hypertension development, and the coupling between STIM-1 (ER Ca2+ sensor) and Orai-1 (channel pore) is a key mechanism to control SOCE through of store-operated Ca2+ channels (SOCCs). However, the role of STIM-1/Orai-1-mediated SOCE and its cross-talk with EtOH-triggered vascular remodeling and hypertension remain poorly understood. We address this subject in the present study by evaluating how chronic EtOH consumption induces alterations in Ca2+ handling via SOCE.


METHODS
Male Wistar Kyoto (WKY) and Spontaneously Hypertensive (SHR) rats were subjected to the intake of increasing EtOH concentrations (5-20%, for 30 days). Systolic blood pressure (SBP) and EtOH concentration were measured; cardiovascular remodeling was assessed by histomorphometry; and function/ expression of STIM-1/Orai-1-mediated Ca2+ influx were evaluated by isometric contraction and western blot experiments.


RESULTS
Compared to the WKY-Control, our results show that: (1) chronic EtOH consumption caused a significant elevation of SBP in both strains; (2) cardiac hypertrophy and hypertrophic aortic wall remodeling much more pronounced in WKY-EtOH; (3) decreased capacity of ER to store and release Ca2+; (4) increased STIM-1/Orai-1-mediated SOCCs activation, which was selectively inhibited by YM-58483; and (5) increased expression of STIM-1 in WKY-EtOH and SHR-Control rats.


CONCLUSIONS
These findings suggest that hypertrophic aortic remodeling and abnormal contraction triggered mainly by Ca2+ overload via STIM-1/Orai-1-mediated SOCE through SOCCs are involved hypertension developed by EtOH consumption.
Departamento de Farmacologia, Escola Paulista de Medicina da Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Guilherme Henrique
GH
Souza Bomfim
Instituto Teófilo Hernando de I+D del Medicamento, Facultad de Medicina de la Universidad Autónoma de Madrid (UAM), Madrid, Spain.
Iago
I
Mendez-Lopez
Instituto Teófilo Hernando de I+D del Medicamento, Facultad de Medicina de la Universidad Autónoma de Madrid (UAM), Madrid, Spain.
Juan Alberto
JA
Arranz-Tagarro
Departamento de Morfologia e Genetica, Escola Paulista de Medicina da Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Adriana Aparecida
AA
Ferraz Carbonel
Departamento de Biofísica, Escola Paulista de Medicina da Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Danilo
D
Roman-Campos
Instituto Teófilo Hernando de I+D del Medicamento, Facultad de Medicina de la Universidad Autónoma de Madrid (UAM), Madrid, Spain.
Juan Fernando
JF
Padín
Instituto Teófilo Hernando de I+D del Medicamento, Facultad de Medicina de la Universidad Autónoma de Madrid (UAM), Madrid, Spain.
Antonio Garcia
AG
Garcia
Departamento de Farmacologia, Escola Paulista de Medicina da Universidade Federal de Sao Paulo (UNIFESP), Sao Paulo, Brazil.
Aron
A
Jurkiewicz
Rua tres de Maio n° 100, 04044-020. Sao Paulo-SP, Brazil.
Neide Hyppolito
NH
Jurkiewicz
D000428:Alcohol Drinking / Q000009:adverse effects*; D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism / Q000503:physiopathology; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000431:Ethanol; D006973:Hypertension / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000503:physiopathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D000071740:ORAI1 Protein / Q000378:metabolism*; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000071737:Stromal Interaction Molecule 1 / Q000378:metabolism*; D013997:Time Factors; D015854:Up-Regulation; D066253:Vascular Remodeling; D014661:Vasoconstriction
D000071740:ORAI1 Protein; C532493:Orai1 protein, rat; C518857:Stim1 protein, rat; D000071737:Stromal Interaction Molecule 1; D000431:Ethanol; D002118:Calcium
Ca2+ handling; STIM-1/Orai-1-mediated SOCCs activation; aortic remodeling; cardiac hypertrophy; chronic EtOH
consumption; hypertension development