Adverse cardiovascular remodeling is particularly prevalent in elderly patients, resulting in poor quality of life and devastating consequences. In response to various physiological and pathological stressors, the cardiac and vascular systems remodel with changes in shape and function that progressively lead to adverse cardiovascular outcomes1. At the cellular level, this pathological remodeling is initiated and sustained by abnormalities in intracellular signaling pathways especially those controlled by calcium (Ca2+)2. Recent studies from both our laboratories have identified a new source of Ca2+ entry in cardiovascular myocytes (i.e., cardiac myocytes; CMs and vascular smooth muscle cells; VSMCs)3-5. This source is controlled by a complex composed of STromal Interaction Molecule 1 (STIM1), a Ca2+ sensor mainly expressed at the endoplasmic reticulum (ER) membrane, which interacts with and activates a new family of Ca2+ selective plasma membrane (PM) channels, the Orai family (Orai1 through 3). The STIM1/Orai1-3 signaling paradigm can either form: i) PM Ca2+ channels activated by ER Ca2+ store depletion (Orai1 homomers) termed Ca2+ release-activated Ca2+ (CRAC) channels, or ii) store-independent Ca2+ channels activated from the cytosolic side by the arachidonate metabolite, leukotrieneC4 (LTC4) and mediated by heteromultimers of Orai1 and Orai3 (named LRC for LTC4-regulated Ca2+)3-7. In different cellular and animal models of cardiac and vascular disorders, we have demonstrated the emergence of the STIM/Orai-mediated Ca2+ signaling that specifically couples to gene transcription and underlies phenotypic changes associated with cardiac and vascular remodeling (i.e. CM growth - cardiac hypertrophy and VSMC proliferation - vascular stenosis respectively)3-5. The targeted manipulation of this local calcium source prevents adverse cardiac and vascular remodeling thus offering new therapeutic perspectives3-5. The goal of this project is the characterization of the molecular processes that are specifically controlled by the different elements of the STIM1/Orai complex in the cardiovascular system. Our recent data indicate that along with Orai1, Orai3, which is exclusive to mammals, is a key component of the STIM1-dependent store- independent Ca2+ selective currents that emerge in pathological cardiovascular myocytes. We thus hypothesize that Orai3 channels more specifically regulate key pathways and gene networks that are activated during cardiovascular remodeling in order to promote cell growth, proliferation and survival. We propose to compare the transcriptional signature of isolated cardiovascular myocytes (i.e., cardiac myocytes and arterial smooth muscle cells) from Stim1 and Orai3 tissue-specific knockout mice and from wild-type mice under normal and pathological conditions of cardiac and vessel remodeling. Together, these exploratory results will support Orai3 targeting in age-related cardiovascular remodeling.
Aging associated cardiovascular remodeling is a major risk factor for heart failure; stroke and no current therapies are specifically directed against preventing the associated changes in cardiovascular myocytes. Research from this proposal will generate better understanding of cardiovascular myocytes physiology, discover new players involved in cardiovascular remodeling and establish Orai3 and its downstream effectors as novel targets for drug therapies aimed at preventing cardiovascular remodeling during aging and other associated vascular diseases.
| Pierro, Cristina; Zhang, Xuexin; Kankeu, Cynthia et al. (2018) Oncogenic KRAS suppresses store-operated Ca2+ entry and ICRAC through ERK pathway-dependent remodelling of STIM expression in colorectal cancer cell lines. Cell Calcium 72:70-80 |
| Johnson, Martin; Trebak, Mohamed (2018) Slow Traffic Makes for Bad Circulation. Hypertension 72:585-587 |
| Ben-Kasus Nissim, Tsipi; Zhang, Xuexin; Elazar, Assaf et al. (2017) Mitochondria control store-operated Ca2+ entry through Na+ and redox signals. EMBO J 36:797-815 |
| Hempel, Nadine; Trebak, Mohamed (2017) Crosstalk between calcium and reactive oxygen species signaling in cancer. Cell Calcium 63:70-96 |
| Trebak, Mohamed; Putney Jr, James W (2017) ORAI Calcium Channels. Physiology (Bethesda) 32:332-342 |
| Tanwar, Jyoti; Trebak, Mohamed; Motiani, Rajender K (2017) Cardiovascular and Hemostatic Disorders: Role of STIM and Orai Proteins in Vascular Disorders. Adv Exp Med Biol 993:425-452 |
| Cai, Xiangyu; Zhou, Yandong; Nwokonko, Robert M et al. (2016) The Orai1 Store-operated Calcium Channel Functions as a Hexamer. J Biol Chem 291:25764-25775 |
| Kassan, Modar; Ait-Aissa, Karima; Radwan, Eman et al. (2016) Essential Role of Smooth Muscle STIM1 in Hypertension and Cardiovascular Dysfunction. Arterioscler Thromb Vasc Biol 36:1900-9 |
| Zhou, Yandong; Cai, Xiangyu; Loktionova, Natalia A et al. (2016) The STIM1-binding site nexus remotely controls Orai1 channel gating. Nat Commun 7:13725 |
| Spinelli, Amy M; Trebak, Mohamed (2016) Orai channel-mediated Ca2+ signals in vascular and airway smooth muscle. Am J Physiol Cell Physiol 310:C402-13 |
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