Altered mitochondrial function, capacitative calcium entry and contractions in the aorta of hypertensive rats

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Mendez-Lopez, Iago
Bomfim, Guilherme H. S. [UNIFESP]
Musial, Diego C. [UNIFESP]
Arranz-Tagarro, Juan A.
Velasco-Martin, Juan P.
Regadera, Javier
Jurkiewicz, Neide H. [UNIFESP]
Jurkiewicz, Aron [UNIFESP]
Garcia, Antonio G.
Padin, J. Fernando
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Objective:It has been suggested that Ca2+ entry through store-operated Ca2+ channels (SOCs) is regulated by a dynamic interplay between the endoplasmic reticulum Ca2+ stores and the mitochondria. These relationships drive the activation and inactivation of SOCs, yet it remains unclear whether this regulation of SOCs by mitochondria is altered in the aorta of spontaneously hypertensive rats (SHRs).Methods:We performed a thorough study of the mitochondrial membrane potential, the ability of mitochondria to deal with cytosolic Ca2+, capacitative Ca2+ entry (CCE), and stromal interaction molecule 1 (STIM1) and calcium release-activated calcium modulator 1 (orai1) protein expression, as well as the contractile capacity of aortic rings, in normotensive Wistar Kyoto rats (WKYs) and SHRs.Results:Changes were observed in aortic tissue and cultured vascular smooth muscle cells isolated from SHRs relative to WKYs, including more depolarized mitochondria, stronger CCE upon the addition of Ca2+, larger cytosolic Ca2+ transients (cytosolic Ca2+ concentration) or aortic ring contraction elicited by endoplasmic reticulum depletion and a significant increase in STIM1 protein expression but not of orai1.Conclusion:These results suggest that the impaired Ca2+ buffering capacity of partially depolarized mitochondria dysregulates CCE, leading to overfilling of the endoplasmic reticulum Ca2+ store through enhanced STIM1/orai1 interactions and an increase in aorta contractions in SHRs. Thus, understanding the implications of the alterations to STIM1/orai1, and their relationship to mitochondria, may aid drug development and therapeutic strategies to treat hypertension, as well as its long-term sequelae in poorly controlled patients.
Journal Of Hypertension. Philadelphia, v. 35, n. 8, p. 1594-1608, 2017.