Abstract
Pathological cardiac remodeling correlates with chronic neurohumoral stimulation and abnormal Ca2+ signaling in cardiomyocytes. Store-operated calcium entry (SOCE) has been described in adult and neonatal murine cardiomyocytes, and Orai1 proteins act as crucial ion-conducting constituents of this calcium entry pathway that can be engaged not only by passive Ca2+ store depletion but also by neurohumoral stimuli such as angiotensin-II. In this study, we, therefore, analyzed the consequences of Orai1 deletion for cardiomyocyte hypertrophy in neonatal and adult cardiomyocytes as well as for other features of pathological cardiac remodeling including cardiac contractile function in vivo. Cellular hypertrophy induced by angiotensin-II in embryonic cardiomyocytes from Orai1-deficient mice was blunted in comparison to cells from litter-matched control mice. Due to lethality of mice with ubiquitous Orai1 deficiency and to selectively analyze the role of Orai1 in adult cardiomyocytes, we generated a cardiomyocyte-specific and temporally inducible Orai1 knockout mouse line (Orai1CM–KO). Analysis of cardiac contractility by pressure-volume loops under basal conditions and of cardiac histology did not reveal differences between Orai1CM–KO mice and controls. Moreover, deletion of Orai1 in cardiomyocytes in adult mice did not protect them from angiotensin-II-induced cardiac remodeling, but cardiomyocyte cross-sectional area and cardiac fibrosis were enhanced. These alterations in the absence of Orai1 go along with blunted angiotensin-II-induced upregulation of the expression of Myoz2 and a lack of rise in angiotensin-II-induced STIM1 and Orai3 expression. In contrast to embryonic cardiomyocytes, where Orai1 contributes to the development of cellular hypertrophy, the results obtained from deletion of Orai1 in the adult myocardium reveal a protective function of Orai1 against the development of angiotensin-II-induced cardiac remodeling, possibly involving signaling via Orai3/STIM1-calcineurin-NFAT related pathways.
Highlights
The main compensatory homeostatic responses to reduction of heart function are activation of the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system [1].Cells 2020, 9, 1092; doi:10.3390/cells9051092 www.mdpi.com/journal/cellsAngiotensin-II (AngII) is able to activate AT1 − receptors which couple to Gq/11, G12/13 − or Gi/o and activates signaling cascades that involve the regulation of [Ca2+ ]i and development of cardiac hypertrophy [2]
Members of the TRPC subfamily of transient receptor potential canonical channels are involved in these processes, and recently a background Ca2+ entry pathway (BGCE) was described in mouse adult cardiomyocytes, which is crucial for the pathological cardiac remodeling but does not modulate cardiac contractility in vivo
Since global Orai1 deletion leads to perinatal lethality in mice [37,52], we utilized prenatal cardiomyocytes (E18.5) for the evaluation of the role of Orai1 in the development of cellular hypertrophy in vitro
Summary
The main compensatory homeostatic responses to reduction of heart function are activation of the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system [1].Cells 2020, 9, 1092; doi:10.3390/cells9051092 www.mdpi.com/journal/cellsAngiotensin-II (AngII) is able to activate AT1 − receptors which couple to Gq/11 , G12/13 − or Gi/o and activates signaling cascades that involve the regulation of [Ca2+ ]i and development of cardiac hypertrophy [2]. Besides its important role for contractile mechanisms, Ca2+ plays a fundamental function as a second messenger. It controls hypertrophic genes, e.g., via the calcineurin-NFAT-pathway by translocation of NFAT into the nucleus [3] and its homeostatic alterations underlie hallmarks (contractile dysfunction and arrhythmias) of heart failure [4]. BGCE is significantly enhanced by AngII treatment and is mediated by TRPC1/TRPC4 channels [9] Another crucial Ca2+ entry pathway into the cells, which can be evoked by receptor agonists leading to phospholipase C activation and depletion by IP3 -sensitive Ca2+ stores, is the so-called store-operated Ca2+ entry (SOCE). This Ca2+ entry pathway was initially identified in non-excitable cells and it is mediated by Ca2+ channels that are activated by depletion of intercellular Ca2+ stores to refill
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