{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,18]],"date-time":"2026-06-18T19:59:53Z","timestamp":1781812793839,"version":"3.54.5"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Cold exposure is associated with oxidative stress and cardiac dysfunction. The endothelin (ET) system, which plays a key role in myocardial homeostasis, may participate in cold exposure-induced cardiovascular dysfunction. This study was designed to examine the role of ET-1 in cold stress-induced cardiac geometric and contractile responses. Wild-type (WT) and ETA receptor knockout (ETAKO) mice were assigned to normal or cold exposure (4\u00b0C) environment for 2 and 5 weeks prior to evaluation of cardiac geometry, contractile, and intracellular Ca2+ properties. Levels of the temperature sensor transient receptor potential vanilloid (TRPV1), mitochondrial proteins for biogenesis and oxidative phosphorylation, including UCP2, HSP90, and PGC1\u03b1 were evaluated. Cold stress triggered cardiac hypertrophy, depressed myocardial contractile capacity, including fractional shortening, peak shortening, and maximal velocity of shortening\/relengthening, reduced intracellular Ca2+ release, prolonged intracellular Ca2+ decay and relengthening duration, generation of ROS and superoxide, as well as apoptosis, the effects of which were blunted by ETAKO. Western blotting revealed downregulated TRPV1 and PGC1\u03b1 as well as upregulated UCP2 and activation of GSK3\u03b2, GATA4, and CREB in cold-stressed WT mouse hearts, which were obliterated by ETAKO. Levels of HSP90, an essential regulator for thermotolerance, were unchanged. The TRPV1 agonist SA13353 attenuated whereas TRPV1 antagonist capsazepine mimicked cold stress- or ET-1-induced cardiac anomalies. The GSK3\u03b2 inhibitor SB216763 ablated cold stress-induced cardiac contractile (but not remodeling) changes and ET-1-induced TRPV1 downregulation. These data suggest that ETAKO protects against cold exposure-induced cardiac remodeling and dysfunction mediated through TRPV1 and mitochondrial function.<\/jats:p>","DOI":"10.1093\/jmcb\/mjs002","type":"journal-article","created":{"date-parts":[[2012,3,23]],"date-time":"2012-03-23T16:11:59Z","timestamp":1332519119000},"page":"97-107","source":"Crossref","is-referenced-by-count":63,"title":["Cardiac-specific knockout of ETA receptor mitigates low ambient temperature-induced cardiac hypertrophy and contractile dysfunction"],"prefix":"10.1093","volume":"4","author":[{"given":"Yingmei","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an710032, China"},{"name":"Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linlin","family":"Li","sequence":"additional","affiliation":[{"name":"Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071, USA"},{"name":"Department of Pharmacology, Xinjiang Medical University, Urumqi, Xinjiang830011, P. 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Sci."},{"key":"2020010305181966200_MJS002C2","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1097\/FJC.0b013e3181993493","article-title":"ETA receptor blockade with atrasentan prevents hypertension with the multitargeted tyrosine kinase inhibitor ABT-869 in telemetry-instrumented rats","volume":"53","author":"Banfor","year":"2009","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"2020010305181966200_MJS002C3","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1139\/Y08-059","article-title":"Endothelin: 20 years from discovery to therapy","volume":"86","author":"Barton","year":"2008","journal-title":"Can. J. Physiol. Pharmacol."},{"key":"2020010305181966200_MJS002C4","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.tips.2008.01.003","article-title":"The Wnt\/frizzled\/GSK-3 beta pathway: a novel therapeutic target for cardiac hypertrophy","volume":"29","author":"Blankesteijn","year":"2008","journal-title":"Trends Pharmacol. Sci."},{"key":"2020010305181966200_MJS002C5","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1152\/japplphysiol.01407.2005","article-title":"Effects of chronic cold exposure on the endothelin system","volume":"100","author":"Chen","year":"2006","journal-title":"J. Appl. Physiol."},{"key":"2020010305181966200_MJS002C6","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ejim.2010.03.001","article-title":"Effects of climatic temperature stress on cardiovascular diseases","volume":"21","author":"Cheng","year":"2010","journal-title":"Eur. J. Intern. Med."},{"key":"2020010305181966200_MJS002C7","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1016\/j.yjmcc.2010.11.020","article-title":"Targeting GSK-3 family members in the heart: a very sharp double-edged sword","volume":"51","author":"Cheng","year":"2011","journal-title":"J. Mol. Cell. 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Pharmacol."},{"key":"2020010305181966200_MJS002C40","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1016\/j.yjmcc.2010.12.007","article-title":"Deficiency in AMP-activated protein kinase exaggerates high fat diet-induced cardiac hypertrophy and contractile dysfunction","volume":"50","author":"Turdi","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"2020010305181966200_MJS002C41","doi-asserted-by":"crossref","first-page":"3617","DOI":"10.1161\/CIRCULATIONAHA.105.556274","article-title":"TRPV1 gene knockout impairs postischemic recovery in isolated perfused heart in mice","volume":"112","author":"Wang","year":"2005","journal-title":"Circulation"},{"key":"2020010305181966200_MJS002C42","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1161\/HYPERTENSIONAHA.108.110197","article-title":"Deletion of transient receptor potential vanilloid type 1 receptors exaggerates renal damage in deoxycorticosterone acetate-salt hypertension","volume":"52","author":"Wang","year":"2008","journal-title":"Hypertension"},{"key":"2020010305181966200_MJS002C43","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1016\/S0092-8674(00)80611-X","article-title":"Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1","volume":"98","author":"Wu","year":"1999","journal-title":"Cell"},{"key":"2020010305181966200_MJS002C44","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1161\/01.CIR.0000140766.52771.6D","article-title":"Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes","volume":"110","author":"Xu","year":"2004","journal-title":"Circulation"},{"key":"2020010305181966200_MJS002C45","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.toxlet.2008.05.005","article-title":"alpha-zearalanol attenuates oxLDL-induced ET-1 gene expression, ET-1 secretion and redox-sensitive intracellular signaling activation in human umbilical vein endothelial cells","volume":"179","author":"Xu","year":"2008","journal-title":"Toxicol. Lett."},{"key":"2020010305181966200_MJS002C46","doi-asserted-by":"crossref","first-page":"130","DOI":"10.1016\/j.cmet.2010.05.015","article-title":"Activation of TRPV1 by dietary capsaicin improves endothelium-dependent vasorelaxation and prevents hypertension","volume":"12","author":"Yang","year":"2010","journal-title":"Cell Metab."},{"key":"2020010305181966200_MJS002C47","doi-asserted-by":"publisher","DOI":"10.1007\/s00484-011-0497-3","article-title":"Daily average temperature and mortality among the elderly: a meta-analysis and systematic review of epidemiological evidence","author":"Yu","year":"2011","journal-title":"Int. J. Biometeorol."},{"key":"2020010305181966200_MJS002C48","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1006\/jsre.2001.6246","article-title":"Endothelin receptor A blockade ameliorates hypothermic ischemia-reperfusion-related microhemodynamic disturbances during liver transplantation in the rat","volume":"102","author":"Zhang","year":"2002","journal-title":"J. Surg. Res."},{"key":"2020010305181966200_MJS002C49","doi-asserted-by":"crossref","first-page":"2407","DOI":"10.1089\/ars.2010.3751","article-title":"Activation of Akt rescues endoplasmic reticulum stress-impaired murine cardiac contractile function via glycogen synthase kinase-3beta-mediated suppression of mitochondrial permeation pore opening","volume":"15","author":"Zhang","year":"2011","journal-title":"Antioxid. 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