Caveolin-1/-3: therapeutic targets for myocardial ischemia/reperfusion injury

  • Yang Yang
  • Zhiqiang Ma
  • Wei Hu
  • Dongjin Wang
  • Shuai Jiang
  • Chongxi Fan
  • Shouyin Di
  • Dong Liu
  • Yang Sun
  • Wei Yi


Myocardial ischemia/reperfusion (I/R) injury is a major cause of morbidity and mortality worldwide. Caveolae, caveolin-1 (Cav-1), and caveolin-3 (Cav-3) are essential for the protective effects of conditioning against myocardial I/R injury. Caveolins are membrane-bound scaffolding proteins that compartmentalize and modulate signal transduction. In this review, we introduce caveolae and caveolins and briefly describe the interactions of caveolins in the cardiovascular diseases. We also review the roles of Cav-1/-3 in protection against myocardial ischemia and I/R injury, and in conditioning. Finally, we suggest several potential research avenues that may be of interest to clinicians and basic scientists. The information included, herein, is potentially useful for the design of future studies and should advance the investigation of caveolins as therapeutic targets.


Myocardial ischemia Caveolins Cardioprotection 



Protein kinase B


Anesthetic preconditioning




Caveolin scaffolding domain


Endothelial nitric oxide synthase


Extracellular signal-regulated kinases 1 and 2


G protein-coupled receptors


Glycogen synthase kinase-3β


Heme oxygenase-1


Ischemic preconditioning


Ischemic postconditioning






Mitogen-activated protein kinases


Mitochondrial permeability transition pore




Phosphoinositide-3 kinase


Protein kinase C


Reperfusion injury salvage kinase


Survivor activating factor enhancement


  1. 1.
    Ahn M, Kim H, Matsumoto Y, Shin T (2006) Increased expression of caveolin-1 and -2 in the hearts of Lewis rats with experimental autoimmune myocarditis. Autoimmunity 39:489–495. doi: 10.1080/08916930600929321 PubMedCrossRefGoogle Scholar
  2. 2.
    Alcalay Y, Hochhauser E, Kliminski V, Dick J, Zahalka MA, Parnes D, Schlesinger H, Abassi Z, Shainberg A, Schindler RF, Brand T, Kessler-Icekson G (2013) Popeye domain containing 1 (Popdc1/Bves) is a caveolae-associated protein involved in ischemia tolerance. PLoS One 8:e71100. doi: 10.1371/journal.pone.0071100 PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Anderson RG, Jacobson K (2002) A role for lipid shells in targeting proteins to caveolae, rafts, and other lipid domains. Science 296:1821–1825. doi: 10.1126/science.1068886 PubMedCrossRefGoogle Scholar
  4. 4.
    Ballard-Croft C, Locklar AC, Kristo G, Lasley RD (2006) Regional myocardial ischemia-induced activation of MAPKs is associated with subcellular redistribution of caveolin and cholesterol. Am J Physiol Heart Circ Physiol 291:H658–H667. doi: 10.1152/ajpheart.01354.2005 PubMedCrossRefGoogle Scholar
  5. 5.
    Bernatchez P, Sharma A, Bauer PM, Marin E, Sessa WC (2011) A noninhibitory mutant of the caveolin-1 scaffolding domain enhances eNOS-derived NO synthesis and vasodilation in mice. J Clin Invest 121:3747–3755. doi: 10.1172/JCI44778 PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Bielawska AE, Shapiro JP, Jiang L, Melkonyan HS, Piot C, Wolfe CL, Tomei LD, Hannun YA, Umansky SR (1997) Ceramide is involved in triggering of cardiomyocyte apoptosis induced by ischemia and reperfusion. Am J Pathol 151:1257–1263PubMedPubMedCentralGoogle Scholar
  7. 7.
    Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM (2005) Glucagon-like peptide 1 can directly protect the heart against ischemia/reperfusion injury. Diabetes 54:146–151PubMedCrossRefGoogle Scholar
  8. 8.
    Bulluck H, Hausenloy DJ (2015) Ischaemic conditioning: are we there yet? Heart 101:1067–1077. doi: 10.1136/heartjnl-2014-306531 PubMedCrossRefGoogle Scholar
  9. 9.
    Cao CM, Zhang Y, Weisleder N, Ferrante C, Wang X, Lv F, Zhang Y, Song R, Hwang M, Jin L, Guo J, Peng W, Li G, Nishi M, Takeshima H, Ma J, Xiao RP (2010) MG53 constitutes a primary determinant of cardiac ischemic preconditioning. Circulation 121:2565–2574. doi: 10.1161/circulationaha.110.954628 PubMedCrossRefGoogle Scholar
  10. 10.
    Cao T, Gao Z, Gu L, Chen M, Yang B, Cao K, Huang H, Li M (2014) AdipoR1/APPL1 potentiates the protective effects of globular adiponectin on angiotensin II-induced cardiac hypertrophy and fibrosis in neonatal rat atrial myocytes and fibroblasts. PLoS One 9:e103793. doi: 10.1371/journal.pone.0103793 PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Cason BA, Gamperl AK, Slocum RE, Hickey RF (1997) Anesthetic-induced preconditioning: previous administration of isoflurane decreases myocardial infarct size in rabbits. Anesthesiology 87:1182–1190. doi: 10.1097/00000542-199711000-00023 PubMedCrossRefGoogle Scholar
  12. 12.
    Chaudhary KR, Cho WJ, Yang F, Samokhvalov V, El-Sikhry HE, Daniel EE, Seubert JM (2013) Effect of ischemia reperfusion injury and epoxyeicosatrienoic acids on caveolin expression in mouse myocardium. J Cardiovasc Pharmacol 61:258–263. doi: 10.1097/FJC.0b013e31827afcee PubMedCrossRefGoogle Scholar
  13. 13.
    Chung TH, Wang SM, Liang JY, Yang SH, Wu JC (2009) The interaction of estrogen receptor alpha and caveolin-3 regulates connexin43 phosphorylation in metabolic inhibition-treated rat cardiomyocytes. Int J Biochem Cell Biol 41:2323–2333. doi: 10.1016/j.biocel.2009.06.001 PubMedCrossRefGoogle Scholar
  14. 14.
    Das M, Cui J, Das DK (2007) Generation of survival signal by differential interaction of p38MAPKalpha and p38MAPKbeta with caveolin-1 and caveolin-3 in the adapted heart. J Mol Cell Cardiol 42:206–213. doi: 10.1016/j.yjmcc.2006.08.118 PubMedCrossRefGoogle Scholar
  15. 15.
    Das M, Das S, Lekli I, Das DK (2012) Caveolin induces cardioprotection through epigenetic regulation. J Cell Mol Med 16:888–895. doi: 10.1111/j.1582-4934.2011.01372.x PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Das M, Das S, Wang P, Powell SR, Das DK (2008) Caveolin and proteasome in tocotrienol mediated myocardial protection. Cell Physiol Biochem 22:287–294. doi: 10.1159/000149807 PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Das M, Gherghiceanu M, Lekli I, Mukherjee S, Popescu LM, Das DK (2008) Essential role of lipid raft in ischemic preconditioning. Cell Physiol Biochem 21:325–334. doi: 10.1159/000129391 PubMedCrossRefGoogle Scholar
  18. 18.
    de Marco MC, Kremer L, Albar JP, Martinez-Menarguez JA, Ballesta J, Garcia-Lopez MA, Marazuela M, Puertollano R, Alonso MA (2001) BENE, a novel raft-associated protein of the MAL proteolipid family, interacts with caveolin-1 in human endothelial-like ECV304 cells. J Biol Chem 276:23009–23017. doi: 10.1074/jbc.M009739200 PubMedCrossRefGoogle Scholar
  19. 19.
    Der P, Cui J, Das DK (2006) Role of lipid rafts in ceramide and nitric oxide signaling in the ischemic and preconditioned hearts. J Mol Cell Cardiol 40:313–320. doi: 10.1016/j.yjmcc.2005.10.005 PubMedCrossRefGoogle Scholar
  20. 20.
    Drab M, Verkade P, Elger M, Kasper M, Lohn M, Lauterbach B, Menne J, Lindschau C, Mende F, Luft FC, Schedl A, Haller H, Kurzchalia TV (2001) Loss of caveolae, vascular dysfunction, and pulmonary defects in caveolin-1 gene-disrupted mice. Science 293:2449–2452. doi: 10.1126/science.1062688 PubMedCrossRefGoogle Scholar
  21. 21.
    Feron O, Balligand JL (2006) Caveolins and the regulation of endothelial nitric oxide synthase in the heart. Cardiovasc Res 69:788–797. doi: 10.1016/j.cardiores.2005.12.014 PubMedCrossRefGoogle Scholar
  22. 22.
    Fiedler K, Parton RG, Kellner R, Etzold T, Simons K (1994) VIP36, a novel component of glycolipid rafts and exocytic carrier vesicles in epithelial cells. EMBO J 13:1729–1740PubMedPubMedCentralGoogle Scholar
  23. 23.
    Fridolfsson HN, Kawaraguchi Y, Ali SS, Panneerselvam M, Niesman IR, Finley JC, Kellerhals SE, Migita MY, Okada H, Moreno AL, Jennings M, Kidd MW, Bonds JA, Balijepalli RC, Ross RS, Patel PM, Miyanohara A, Chen Q, Lesnefsky EJ, Head BP, Roth DM, Insel PA, Patel HH (2012) Mitochondria-localized caveolin in adaptation to cellular stress and injury. FASEB J 26:4637–4649. doi: 10.1096/fj.12-215798 PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Gandolfini MP, Coupaye M, Bouaziz E, Dehoux M, Hajage D, Lacorte JM, Ledoux S (2015) Cardiovascular changes after gastric bypass surgery: involvement of increased secretions of glucagon-like peptide-1 and brain natriuretic peptide. Obes Surg. doi: 10.1007/s11695-015-1643-5 PubMedGoogle Scholar
  25. 25.
    Garcia-Cardena G, Martasek P, Masters BS, Skidd PM, Couet J, Li S, Lisanti MP, Sessa WC (1997) Dissecting the interaction between nitric oxide synthase (NOS) and caveolin. Functional significance of the nos caveolin binding domain in vivo. J Biol Chem 272:25437–25440. doi: 10.1074/jbc.272.41.25437 PubMedCrossRefGoogle Scholar
  26. 26.
    Gazzerro E, Sotgia F, Bruno C, Lisanti MP, Minetti C (2010) Caveolinopathies: from the biology of caveolin-3 to human diseases. Eur J Hum Genet 18:137–145. doi: 10.1038/ejhg.2009.103 PubMedCrossRefGoogle Scholar
  27. 27.
    Giusti B, Marini M, Rossi L, Lapini I, Magi A, Capalbo A, Lapalombella R, di Tullio S, Samaja M, Esposito F, Margonato V, Boddi M, Abbate R, Veicsteinas A (2009) Gene expression profile of rat left ventricles reveals persisting changes following chronic mild exercise protocol: implications for cardioprotection. BMC Genom 10:342. doi: 10.1186/1471-2164-10-342 CrossRefGoogle Scholar
  28. 28.
    Glenney JR Jr, Zokas L (1989) Novel tyrosine kinase substrates from Rous sarcoma virus-transformed cells are present in the membrane skeleton. J Cell Biol 108:2401–2408. doi: 10.1083/jcb.108.6.2401 PubMedCrossRefGoogle Scholar
  29. 29.
    Hagiwara Y, Sasaoka T, Araishi K, Imamura M, Yorifuji H, Nonaka I, Ozawa E, Kikuchi T (2000) Caveolin-3 deficiency causes muscle degeneration in mice. Hum Mol Genet 9:3047–3054. doi: 10.1093/hmg/9.20.3047 PubMedCrossRefGoogle Scholar
  30. 30.
    Halestrap AP (2009) What is the mitochondrial permeability transition pore? J Mol Cell Cardiol 46:821–831. doi: 10.1016/j.yjmcc.2009.02.021 PubMedCrossRefGoogle Scholar
  31. 31.
    Hausenloy DJ, Tsang A, Yellon DM (2005) The reperfusion injury salvage kinase pathway: a common target for both ischemic preconditioning and postconditioning. Trends Cardiovasc Med 15:69–75. doi: 10.1016/j.tcm.2005.03.001 PubMedCrossRefGoogle Scholar
  32. 32.
    Hausenloy DJ, Yellon DM (2011) The therapeutic potential of ischemic conditioning: an update. Nat Rev Cardiol 8:619–629. doi: 10.1038/nrcardio.2011.85 PubMedCrossRefGoogle Scholar
  33. 33.
    Hayashi T, Arimura T, Ueda K, Shibata H, Hohda S, Takahashi M, Hori H, Koga Y, Oka N, Imaizumi T, Yasunami M, Kimura A (2004) Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy. Biochem Biophys Res Commun 313:178–184. doi: 10.1016/j.bbrc.2003.11.101 PubMedCrossRefGoogle Scholar
  34. 34.
    Head BP, Patel HH, Roth DM, Lai NC, Niesman IR, Farquhar MG, Insel PA (2005) G-protein-coupled receptor signaling components localize in both sarcolemmal and intracellular caveolin-3-associated microdomains in adult cardiac myocytes. J Biol Chem 280:31036–31044. doi: 10.1074/jbc.M502540200 PubMedCrossRefGoogle Scholar
  35. 35.
    Hernandez-Resendiz S, Zazueta C (2014) PHO-ERK1/2 interaction with mitochondria regulates the permeability transition pore in cardioprotective signaling. Life Sci 108:13–21. doi: 10.1016/j.lfs.2014.04.037 PubMedCrossRefGoogle Scholar
  36. 36.
    Heusch G (2015) Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning. Circ Res 116:674–699. doi: 10.1161/circresaha.116.305348 PubMedCrossRefGoogle Scholar
  37. 37.
    Heusch G, Botker HE, Przyklenk K, Redington A, Yellon D (2015) Remote ischemic conditioning. J Am Coll Cardiol 65:177–195. doi: 10.1016/j.jacc.2014.10.031 PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Hnasko R, Lisanti MP (2003) The biology of caveolae: lessons from caveolin knockout mice and implications for human disease. Mol Interv 3:445–464. doi: 10.1124/mi.3.8.445 PubMedCrossRefGoogle Scholar
  39. 39.
    Horikawa YT, Panneerselvam M, Kawaraguchi Y, Tsutsumi YM, Ali SS, Balijepalli RC, Murray F, Head BP, Niesman IR, Rieg T, Vallon V, Insel PA, Patel HH, Roth DM (2011) Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling. J Am Coll Cardiol 57:2273–2283. doi: 10.1016/j.jacc.2010.12.032 PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Horikawa YT, Patel HH, Tsutsumi YM, Jennings MM, Kidd MW, Hagiwara Y, Ishikawa Y, Insel PA, Roth DM (2008) Caveolin-3 expression and caveolae are required for isoflurane-induced cardiac protection from hypoxia and ischemia/reperfusion injury. J Mol Cell Cardiol 44:123–130. doi: 10.1016/j.yjmcc.2007.10.003 PubMedCrossRefGoogle Scholar
  41. 41.
    Hsieh SR, Hsu CS, Lu CH, Chen WC, Chiu CH, Liou YM (2013) Epigallocatechin-3-gallate-mediated cardioprotection by Akt/GSK-3beta/caveolin signalling in H9c2 rat cardiomyoblasts. J Biomed Sci 20:86. doi: 10.1186/1423-0127-20-86 PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Hsieh SR, Tsai DC, Chen JY, Tsai SW, Liou YM (2009) Green tea extract protects rats against myocardial infarction associated with left anterior descending coronary artery ligation. Pflugers Arch 458:631–642. doi: 10.1007/s00424-009-0655-1 PubMedCrossRefGoogle Scholar
  43. 43.
    Jasmin JF, Rengo G, Lymperopoulos A, Gupta R, Eaton GJ, Quann K, Gonzales DM, Mercier I, Koch WJ, Lisanti MP (2011) Caveolin-1 deficiency exacerbates cardiac dysfunction and reduces survival in mice with myocardial infarction. Am J Physiol Heart Circ Physiol 300:H1274–H1281. doi: 10.1152/ajpheart.01173.2010 PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K (2006) Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 116:1784–1792. doi: 10.1172/jci29126 PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Kersten JR, Schmeling TJ, Pagel PS, Gross GJ, Warltier DC (1997) Isoflurane mimics ischemic preconditioning via activation of K(ATP) channels: reduction of myocardial infarct size with an acute memory phase. Anesthesiology 87:361–370. doi: 10.1097/00000542-199708000-00024 PubMedCrossRefGoogle Scholar
  46. 46.
    Kim HA, Kim KH, Lee RA (2006) Expression of caveolin-1 is correlated with Akt-1 in colorectal cancer tissues. Exp Mol Pathol 80:165–170. doi: 10.1016/j.yexmp.2005.09.001 PubMedCrossRefGoogle Scholar
  47. 47.
    Koneru S, Penumathsa SV, Thirunavukkarasu M, Samuel SM, Zhan L, Han Z, Maulik G, Das DK, Maulik N (2007) Redox regulation of ischemic preconditioning is mediated by the differential activation of caveolins and their association with eNOS and GLUT-4. Am J Physiol Heart Circ Physiol 292:H2060–H2072. doi: 10.1152/ajpheart.01169.2006 PubMedCrossRefGoogle Scholar
  48. 48.
    Krajewska WM, Maslowska I (2004) Caveolins: structure and function in signal transduction. Cell Mol Biol Lett 9:195–220PubMedGoogle Scholar
  49. 49.
    Lacerda L, Somers S, Opie LH, Lecour S (2009) Ischaemic postconditioning protects against reperfusion injury via the SAFE pathway. Cardiovasc Res 84:201–208. doi: 10.1093/cvr/cvp274 PubMedCrossRefGoogle Scholar
  50. 50.
    Lamont KT, Somers S, Lacerda L, Opie LH, Lecour S (2011) Is red wine a SAFE sip away from cardioprotection? Mechanisms involved in resveratrol- and melatonin-induced cardioprotection. J Pineal Res 50:374–380. doi: 10.1111/j.1600-079X.2010.00853.x PubMedCrossRefGoogle Scholar
  51. 51.
    Lang XE, Wang X, Zhang KR, Lv JY, Jin JH, Li QS (2013) Isoflurane preconditioning confers cardioprotection by activation of ALDH2. PLoS One 8:e52469. doi: 10.1371/journal.pone.0052469 PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Li S, Okamoto T, Chun M, Sargiacomo M, Casanova JE, Hansen SH, Nishimoto I, Lisanti MP (1995) Evidence for a regulated interaction between heterotrimeric G proteins and caveolin. J Biol Chem 270:15693–15701PubMedCrossRefGoogle Scholar
  53. 53.
    Liou YM, Hsieh SR, Wu TJ, Chen JY (2010) Green tea extract given before regional myocardial ischemia–reperfusion in rats improves myocardial contractility by attenuating calcium overload. Pflugers Arch 460:1003–1014. doi: 10.1007/s00424-010-0881-6 PubMedCrossRefGoogle Scholar
  54. 54.
    Lisanti MP, Scherer PE, Vidugiriene J, Tang Z, Hermanowski-Vosatka A, Tu YH, Cook RF, Sargiacomo M (1994) Characterization of caveolin-rich membrane domains isolated from an endothelial-rich source: implications for human disease. J Cell Biol 126:111–126. doi: 10.1083/jcb.126.1.111 PubMedCrossRefGoogle Scholar
  55. 55.
    Lochner A, Huisamen B, Nduhirabandi F (2013) Cardioprotective effect of melatonin against ischaemia/reperfusion damage. Front Biosci (Elite Ed) 5:305–315CrossRefGoogle Scholar
  56. 56.
    Lu Q, Yi X, Cheng X, Sun X, Yang X (2014) Melatonin protects against myocardial hypertrophy induced by lipopolysaccharide. In Vitro Cell Dev Biol Anim 51:353–360. doi: 10.1007/s11626-014-9844-0 PubMedCrossRefGoogle Scholar
  57. 57.
    Mayor S, Rao M (2004) Rafts: scale-dependent, active lipid organization at the cell surface. Traffic 5:231–240. doi: 10.1111/j.1600-0854.2004.00172.x PubMedCrossRefGoogle Scholar
  58. 58.
    Minetti C, Bado M, Broda P, Sotgia F, Bruno C, Galbiati F, Volonte D, Lucania G, Pavan A, Bonilla E, Lisanti MP, Cordone G (2002) Impairment of caveolae formation and T-system disorganization in human muscular dystrophy with caveolin-3 deficiency. Am J Pathol 160:265–270. doi: 10.1016/s0002-9440(10)64370-2 PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Mora R, Bonilha VL, Marmorstein A, Scherer PE, Brown D, Lisanti MP, Rodriguez-Boulan E (1999) Caveolin-2 localizes to the golgi complex but redistributes to plasma membrane, caveolae, and rafts when co-expressed with caveolin-1. J Biol Chem 274:25708–25717. doi: 10.1074/jbc.274.36.25708 PubMedCrossRefGoogle Scholar
  60. 60.
    Ohsawa Y, Toko H, Katsura M, Morimoto K, Yamada H, Ichikawa Y, Murakami T, Ohkuma S, Komuro I, Sunada Y (2004) Overexpression of P104L mutant caveolin-3 in mice develops hypertrophic cardiomyopathy with enhanced contractility in association with increased endothelial nitric oxide synthase activity. Hum Mol Genet 13:151–157. doi: 10.1093/hmg/ddh014 PubMedCrossRefGoogle Scholar
  61. 61.
    Oka N, Yamamoto M, Schwencke C, Kawabe J, Ebina T, Ohno S, Couet J, Lisanti MP, Ishikawa Y (1997) Caveolin interaction with protein kinase C. Isoenzyme-dependent regulation of kinase activity by the caveolin scaffolding domain peptide. J Biol Chem 272:33416–33421. doi: 10.1074/jbc.272.52.33416 PubMedCrossRefGoogle Scholar
  62. 62.
    Okada-Iwabu M, Yamauchi T, Iwabu M, Honma T, Hamagami K, Matsuda K, Yamaguchi M, Tanabe H, Kimura-Someya T, Shirouzu M, Ogata H, Tokuyama K, Ueki K, Nagano T, Tanaka A, Yokoyama S, Kadowaki T (2013) A small-molecule AdipoR agonist for type 2 diabetes and short life in obesity. Nature 503:493–499. doi: 10.1038/nature12656 PubMedCrossRefGoogle Scholar
  63. 63.
    Ovize M, Baxter GF, Di Lisa F, Ferdinandy P, Garcia-Dorado D, Hausenloy DJ, Heusch G, Vinten-Johansen J, Yellon DM, Schulz R (2010) Postconditioning and protection from reperfusion injury: where do we stand? Position paper from the Working Group of Cellular Biology of the Heart of the European Society of Cardiology. Cardiovasc Res 87:406–423. doi: 10.1093/cvr/cvq129 PubMedCrossRefGoogle Scholar
  64. 64.
    Panneerselvam M, Patel HH, Roth DM (2012) Caveolins and heart diseases. Adv Exp Med Biol 729:145–156. doi: 10.1007/978-1-4614-1222-9_10 PubMedCrossRefGoogle Scholar
  65. 65.
    Park DS, Woodman SE, Schubert W, Cohen AW, Frank PG, Chandra M, Shirani J, Razani B, Tang B, Jelicks LA, Factor SM, Weiss LM, Tanowitz HB, Lisanti MP (2002) Caveolin-1/3 double-knockout mice are viable, but lack both muscle and non-muscle caveolae, and develop a severe cardiomyopathic phenotype. Am J Pathol 160:2207–2217. doi: 10.1016/s0002-9440(10)61168-6 PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Parolini I, Sargiacomo M, Galbiati F, Rizzo G, Grignani F, Engelman JA, Okamoto T, Ikezu T, Scherer PE, Mora R, Rodriguez-Boulan E, Peschle C, Lisanti MP (1999) Expression of caveolin-1 is required for the transport of caveolin-2 to the plasma membrane. Retention of caveolin-2 at the level of the Golgi complex. J Biol Chem 274:25718–25725. doi: 10.1074/jbc.274.36.25718 PubMedCrossRefGoogle Scholar
  67. 67.
    Parton RG, Simons K (2007) The multiple faces of caveolae. Nat Rev Mol Cell Biol 8:185–194. doi: 10.1038/nrm2122 PubMedCrossRefGoogle Scholar
  68. 68.
    Patel HH, Head BP, Petersen HN, Niesman IR, Huang D, Gross GJ, Insel PA, Roth DM (2006) Protection of adult rat cardiac myocytes from ischemic cell death: role of caveolar microdomains and delta-opioid receptors. Am J Physiol Heart Circ Physiol 291:H344–H350. doi: 10.1152/ajpheart.01100.2005 PubMedCrossRefGoogle Scholar
  69. 69.
    Patel HH, Murray F, Insel PA (2008) Caveolae as organizers of pharmacologically relevant signal transduction molecules. Annu Rev Pharmacol Toxicol 48:359–391. doi: 10.1146/annurev.pharmtox.48.121506.124841 PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Patel HH, Tsutsumi YM, Head BP, Niesman IR, Jennings M, Horikawa Y, Huang D, Moreno AL, Patel PM, Insel PA, Roth DM (2007) Mechanisms of cardiac protection from ischemia/reperfusion injury: a role for caveolae and caveolin-1. FASEB J 21:1565–1574. doi: 10.1096/fj.06-7719com PubMedCrossRefGoogle Scholar
  71. 71.
    Pawson T, Scott JD (1997) Signaling through scaffold, anchoring, and adaptor proteins. Science 278:2075–2080. doi: 10.1126/science.278.5346.2075 PubMedCrossRefGoogle Scholar
  72. 72.
    Peart JN, Gross ER, Gross GJ (2005) Opioid-induced preconditioning: recent advances and future perspectives. Vascul Pharmacol 42:211–218. doi: 10.1016/j.vph.2005.02.003 PubMedCrossRefGoogle Scholar
  73. 73.
    Peart JN, Pepe S, Reichelt ME, Beckett N, See Hoe L, Ozberk V, Niesman IR, Patel HH, Headrick JP (2014) Dysfunctional survival-signaling and stress-intolerance in aged murine and human myocardium. Exp Gerontol 50:72–81. doi: 10.1016/j.exger.2013.11.015 PubMedCrossRefGoogle Scholar
  74. 74.
    Raikar LS, Vallejo J, Lloyd PG, Hardin CD (2006) Overexpression of caveolin-1 results in increased plasma membrane targeting of glycolytic enzymes: the structural basis for a membrane associated metabolic compartment. J Cell Biochem 98:861–871. doi: 10.1002/jcb.20732 PubMedCrossRefGoogle Scholar
  75. 75.
    Rassaf T, Schulz R (2015) Mitochondrias’ sense of SNO-pathway to cardioprotection in ischemic preconditioning. Cardiovasc Res 106:182–183. doi: 10.1093/cvr/cvv115 PubMedCrossRefGoogle Scholar
  76. 76.
    Ratajczak P, Damy T, Heymes C, Oliviero P, Marotte F, Robidel E, Sercombe R, Boczkowski J, Rappaport L, Samuel JL (2003) Caveolin-1 and -3 dissociations from caveolae to cytosol in the heart during aging and after myocardial infarction in rat. Cardiovasc Res 57:358–369. doi: 10.1016/S0008-6363(02)00660-0 PubMedCrossRefGoogle Scholar
  77. 77.
    Razani B, Wang XB, Engelman JA, Battista M, Lagaud G, Zhang XL, Kneitz B, Hou H Jr, Christ GJ, Edelmann W, Lisanti MP (2002) Caveolin-2-deficient mice show evidence of severe pulmonary dysfunction without disruption of caveolae. Mol Cell Biol 22:2329–2344. doi: 10.1128/MCB.22.7.2329-2344.2002 PubMedPubMedCentralCrossRefGoogle Scholar
  78. 78.
    Razani B, Woodman SE, Lisanti MP (2002) Caveolae: from cell biology to animal physiology. Pharmacol Rev 54:431–467. doi: 10.1124/pr.54.3.431 PubMedCrossRefGoogle Scholar
  79. 79.
    Rothberg KG, Heuser JE, Donzell WC, Ying YS, Glenney JR, Anderson RG (1992) Caveolin, a protein component of caveolae membrane coats. Cell 68:673–682. doi: 10.1016/0092-8674(92)90143-Z PubMedCrossRefGoogle Scholar
  80. 80.
    Ruiz-Meana M, Nunez E, Miro-Casas E, Martinez-Acedo P, Barba I, Rodriguez-Sinovas A, Inserte J, Fernandez-Sanz C, Hernando V, Vazquez J, Garcia-Dorado D (2014) Ischemic preconditioning protects cardiomyocyte mitochondria through mechanisms independent of cytosol. J Mol Cell Cardiol 68:79–88. doi: 10.1016/j.yjmcc.2014.01.001 PubMedCrossRefGoogle Scholar
  81. 81.
    Salzer U, Prohaska R (2001) Stomatin, flotillin-1, and flotillin-2 are major integral proteins of erythrocyte lipid rafts. Blood 97:1141–1143. doi: 10.1182/blood.V97.4.1141 PubMedCrossRefGoogle Scholar
  82. 82.
    Sanguinetti AR, Cao H, Corley Mastick C (2003) Fyn is required for oxidative- and hyperosmotic-stress-induced tyrosine phosphorylation of caveolin-1. Biochem J 376:159–168. doi: 10.1042/bj20030336 PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Sanguinetti AR, Mastick CC (2003) c-Abl is required for oxidative stress-induced phosphorylation of caveolin-1 on tyrosine 14. Cell Signal 15:289–298. doi: 10.1016/S0898-6568(02)00090-6 PubMedCrossRefGoogle Scholar
  84. 84.
    Sanon VP, Sawaki D, Mjaatvedt CH, Jourdan-Le Saux C (2015) Myocardial tissue caveolae. Compr Physiol 5:871–886. doi: 10.1002/cphy.c140050 PubMedCrossRefGoogle Scholar
  85. 85.
    Scherer PE, Okamoto T, Chun M, Nishimoto I, Lodish HF, Lisanti MP (1996) Identification, sequence, and expression of caveolin-2 defines a caveolin gene family. Proc Natl Acad Sci USA 93:131–135. doi: 10.1073/pnas.93.1.131 PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Schilling JM, Horikawa YT, Zemljic-Harpf AE, Vincent KP, Tyan L, Yu JK, McCulloch AD, Balijepalli RC, Patel HH, Roth DM (2016) Electrophysiology and metabolism of caveolin-3-overexpressing mice. Basic Res Cardiol 111:28. doi: 10.1007/s00395-016-0542-9 PubMedCrossRefGoogle Scholar
  87. 87.
    Schilling JM, Roth DM, Patel HH (2015) Caveolins in cardioprotection—translatability and mechanisms. Br J Pharmacol 172:2114–2125. doi: 10.1111/bph.13009 PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Schultz JE, Hsu AK, Gross GJ (1998) Ischemic preconditioning in the intact rat heart is mediated by delta 1- but not mu- or kappa-opioid receptors. Circulation 97:1282–1289. doi: 10.1161/01.CIR.97.13.1282 PubMedCrossRefGoogle Scholar
  89. 89.
    See Hoe LE, Schilling JM, Tarbit E, Kiessling CJ, Busija AR, Niesman IR, Du Toit E, Ashton KJ, Roth DM, Headrick JP, Patel HH, Peart JN (2014) Sarcolemmal cholesterol and caveolin-3 dependence of cardiac function, ischemic tolerance, and opioidergic cardioprotection. Am J Physiol Heart Circ Physiol 307:H895–H903. doi: 10.1152/ajpheart.00081.2014 PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Sehirli AO, Koyun D, Tetik S, Ozsavci D, Yiginer O, Cetinel S, Tok OE, Kaya Z, Akkiprik M, Kilic E, Sener G (2013) Melatonin protects against ischemic heart failure in rats. J Pineal Res 55:138–148. doi: 10.1111/jpi.12054 PubMedCrossRefGoogle Scholar
  91. 91.
    Shahabi P, Siest G, Visvikis-siest S (2014) Influence of inflammation on cardiovascular protective effects of cytochrome P450 epoxygenase-derived epoxyeicosatrienoic acids. Drug Metab Rev 46:33–56. doi: 10.3109/03602532.2013.837916 PubMedCrossRefGoogle Scholar
  92. 92.
    Shi Y, Pritchard KA Jr, Holman P, Rafiee P, Griffith OW, Kalyanaraman B, Baker JE (2000) Chronic myocardial hypoxia increases nitric oxide synthase and decreases caveolin-3. Free Radic Biol Med 29:695–703. doi: 10.1016/S0891-5849(00)00364-6 PubMedCrossRefGoogle Scholar
  93. 93.
    Shimizu T, Suzuki S, Sato A, Nakamura Y, Ikeda K, Saitoh SI, Misaka S, Shishido T, Kubota I, Takeishi Y (2015) Cardio-protective effects of pentraxin 3 produced from bone marrow-derived cells against ischemia/reperfusion injury. J Mol Cell Cardiol 89:306–313. doi: 10.1016/j.yjmcc.2015.10.013 PubMedCrossRefGoogle Scholar
  94. 94.
    Shiomi M, Miyamae M, Takemura G, Kaneda K, Inamura Y, Onishi A, Koshinuma S, Momota Y, Minami T, Figueredo VM (2014) Induction of autophagy restores the loss of sevoflurane cardiac preconditioning seen with prolonged ischemic insult. Eur J Pharmacol 724:58–66. doi: 10.1016/j.ejphar.2013.12.027 PubMedCrossRefGoogle Scholar
  95. 95.
    Smart EJ, Graf GA, McNiven MA, Sessa WC, Engelman JA, Scherer PE, Okamoto T, Lisanti MP (1999) Caveolins, liquid-ordered domains, and signal transduction. Mol Cell Biol 19:7289–7304PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Sonne DP, Engstrom T, Treiman M (2008) Protective effects of GLP-1 analogues exendin-4 and GLP-1(9-36) amide against ischemia–reperfusion injury in rat heart. Regul Pept 146:243–249. doi: 10.1016/j.regpep.2007.10.001 PubMedCrossRefGoogle Scholar
  97. 97.
    Sotgia F, Martinez-Outschoorn UE, Howell A, Pestell RG, Pavlides S, Lisanti MP (2012) Caveolin-1 and cancer metabolism in the tumor microenvironment: markers, models, and mechanisms. Annu Rev Pathol 7:423–467. doi: 10.1146/annurev-pathol-011811-120856 PubMedCrossRefGoogle Scholar
  98. 98.
    Sun J, Nguyen T, Aponte AM, Menazza S, Kohr MJ, Roth DM, Patel HH, Murphy E, Steenbergen C (2015) Ischaemic preconditioning preferentially increases protein S-nitrosylation in subsarcolemmal mitochondria. Cardiovasc Res 106:227–236. doi: 10.1093/cvr/cvv044 PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Swaney JS, Patel HH, Yokoyama U, Head BP, Roth DM, Insel PA (2006) Focal adhesions in (myo)fibroblasts scaffold adenylyl cyclase with phosphorylated caveolin. J Biol Chem 281:17173–17179. doi: 10.1074/jbc.M513097200 PubMedCrossRefGoogle Scholar
  100. 100.
    Tang Z, Scherer PE, Okamoto T, Song K, Chu C, Kohtz DS, Nishimoto I, Lodish HF, Lisanti MP (1996) Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle. J Biol Chem 271:2255–2261PubMedCrossRefGoogle Scholar
  101. 101.
    Tonkovic-Capin M, Gross GJ, Bosnjak ZJ, Tweddell JS, Fitzpatrick CM, Baker JE (2002) Delayed cardioprotection by isoflurane: role of K(ATP) channels. Am J Physiol Heart Circ Physiol 283:H61–H68. doi: 10.1152/ajpheart.01040.2001 PubMedCrossRefGoogle Scholar
  102. 102.
    Tsutsumi YM, Horikawa YT, Jennings MM, Kidd MW, Niesman IR, Yokoyama U, Head BP, Hagiwara Y, Ishikawa Y, Miyanohara A, Patel PM, Insel PA, Patel HH, Roth DM (2008) Cardiac-specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning. Circulation 118:1979–1988. doi: 10.1161/circulationaha.108.788331 PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Tsutsumi YM, Kawaraguchi Y, Horikawa YT, Niesman IR, Kidd MW, Chin-Lee B, Head BP, Patel PM, Roth DM, Patel HH (2010) Role of caveolin-3 and glucose transporter-4 in isoflurane-induced delayed cardiac protection. Anesthesiology 112:1136–1145. doi: 10.1097/ALN.0b013e3181d3d624 PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Tsutsumi YM, Kawaraguchi Y, Niesman IR, Patel HH, Roth DM (2010) Opioid-induced preconditioning is dependent on caveolin-3 expression. Anesth Analg 111:1117–1121. doi: 10.1213/ANE.0b013e3181f3351a PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Tsutsumi YM, Tsutsumi R, Hamaguchi E, Sakai Y, Kasai A, Ishikawa Y, Yokoyama U, Tanaka K (2014) Exendin-4 ameliorates cardiac ischemia/reperfusion injury via caveolae and caveolins-3. Cardiovasc Diabetol 13:132. doi: 10.1186/s12933-014-0132-9 PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Tsutsumi YM, Tsutsumi R, Horikawa YT, Sakai Y, Hamaguchi E, Ishikawa Y, Yokoyama U, Kasai A, Kambe N, Tanaka K (2014) Geranylgeranylacetone protects the heart via caveolae and caveolin-3. Life Sci 101:43–48. doi: 10.1016/j.lfs.2014.02.019 PubMedCrossRefGoogle Scholar
  107. 107.
    Tsutsumi YM, Tsutsumi R, Horikawa YT, Sakai Y, Hamaguchi E, Kitahata H, Kasai A, Kambe N, Tanaka K (2014) Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3. J Anesth 28:733–739. doi: 10.1007/s00540-014-1816-8 PubMedCrossRefGoogle Scholar
  108. 108.
    Umegaki E, Kuramoto T, Kojima Y, Nouda S, Ishida K, Takeuchi T, Inoue T, Tokioka S, Higuchi K (2014) Geranylgeranylacetone, a gastromucoprotective drug, protects against NSAID-induced esophageal, gastroduodenal and small intestinal mucosal injury in healthy subjects: a prospective randomized study involving a comparison with famotidine. Intern Med 53:283–290. doi: 10.2169/internalmedicine.53.1572 PubMedCrossRefGoogle Scholar
  109. 109.
    Vatta M, Ackerman MJ, Ye B, Makielski JC, Ughanze EE, Taylor EW, Tester DJ, Balijepalli RC, Foell JD, Li Z, Kamp TJ, Towbin JA (2006) Mutant caveolin-3 induces persistent late sodium current and is associated with long-QT syndrome. Circulation 114:2104–2112. doi: 10.1161/circulationaha.106.635268 PubMedCrossRefGoogle Scholar
  110. 110.
    Volonte D, Galbiati F, Li S, Nishiyama K, Okamoto T, Lisanti MP (1999) Flotillins/cavatellins are differentially expressed in cells and tissues and form a hetero-oligomeric complex with caveolins in vivo. Characterization and epitope-mapping of a novel flotillin-1 monoclonal antibody probe. J Biol Chem 274:12702–12709. doi: 10.1074/jbc.274.18.12702 PubMedCrossRefGoogle Scholar
  111. 111.
    Wang J, Schilling JM, Niesman IR, Headrick JP, Finley JC, Kwan E, Patel PM, Head BP, Roth DM, Yue Y, Patel HH (2014) Cardioprotective trafficking of caveolin to mitochondria is Gi-protein dependent. Anesthesiology 121:538–548. doi: 10.1097/aln.0000000000000295 PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Wang X, Yuan B, Dong W, Yang B, Yang Y, Lin X, Gong G (2014) Induction of heat-shock protein 70 expression by geranylgeranylacetone shows cytoprotective effects in cardiomyocytes of mice under humid heat stress. PLoS One 9:e93536. doi: 10.1371/journal.pone.0093536 PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Wang Y, Wang X, Jasmin JF, Lau WB, Li R, Yuan Y, Yi W, Chuprun K, Lisanti MP, Koch WJ, Gao E, Ma XL (2012) Essential role of caveolin-3 in adiponectin signalsome formation and adiponectin cardioprotection. Arterioscler Thromb Vasc Biol 32:934–942. doi: 10.1161/atvbaha.111.242164 PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Way M, Parton RG (1995) M-caveolin, a muscle-specific caveolin-related protein. FEBS Lett 376:108–112. doi: 10.1016/0014-5793(95)01256-7 PubMedCrossRefGoogle Scholar
  115. 115.
    Williams TM, Lisanti MP (2004) The caveolin proteins. Genome Biol 5:214. doi: 10.1186/gb-2004-5-3-214 PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Yang G, Dong Z, Xu H, Wang C, Li H, Li Z, Li F (2015) Structural study of caveolin-1 intramembrane domain by circular dichroism and nuclear magnetic resonance. Biopolymers 104:11–20. doi: 10.1002/bip.22597 PubMedCrossRefGoogle Scholar
  117. 117.
    Yang Y, Duan W, Jin Z, Yi W, Yan J, Zhang S, Wang N, Liang Z, Li Y, Chen W, Yi D, Yu S (2013) JAK2/STAT3 activation by melatonin attenuates the mitochondrial oxidative damage induced by myocardial ischemia/reperfusion injury. J Pineal Res 55:275–286. doi: 10.1111/jpi.12070 PubMedCrossRefGoogle Scholar
  118. 118.
    Yao Y, Hong S, Zhou H, Yuan T, Zeng R, Liao K (2009) The differential protein and lipid compositions of noncaveolar lipid microdomains and caveolae. Cell Res 19:497–506. doi: 10.1038/cr.2009.27 PubMedCrossRefGoogle Scholar
  119. 119.
    Young LH, Ikeda Y, Lefer AM (2001) Caveolin-1 peptide exerts cardioprotective effects in myocardial ischemia–reperfusion via nitric oxide mechanism. Am J Physiol Heart Circ Physiol 280:H2489–H2495PubMedGoogle Scholar
  120. 120.
    Yu H, Yang Z, Pan S, Yang Y, Tian J, Wang L, Sun W (2015) Hypoxic preconditioning promotes the translocation of protein kinase C epsilon binding with caveolin-3 at cell membrane not mitochondrial in rat heart. Cell Cycle 14:3557–3565. doi: 10.1080/15384101.2015.1084446 PubMedCrossRefGoogle Scholar
  121. 121.
    Zhang J, Liem DA, Mueller M, Wang Y, Zong C, Deng N, Vondriska TM, Korge P, Drews O, Maclellan WR, Honda H, Weiss JN, Apweiler R, Ping P (2008) Altered proteome biology of cardiac mitochondria under stress conditions. J Proteome Res 7:2204–2214. doi: 10.1021/pr070371f PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Zhang Y, Lv F, Jin L, Peng W, Song R, Ma J, Cao CM, Xiao RP (2011) MG53 participates in ischaemic postconditioning through the RISK signalling pathway. Cardiovasc Res 91:108–115. doi: 10.1093/cvr/cvr029 PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Zhao J, Wang F, Zhang Y, Jiao L, Lau WB, Wang L, Liu B, Gao E, Koch WJ, Ma XL, Wang Y (2013) Sevoflurane preconditioning attenuates myocardial ischemia/reperfusion injury via caveolin-3-dependent cyclooxygenase-2 inhibition. Circulation 128:S121–S129. doi: 10.1161/circulationaha.112.000045 PubMedCrossRefGoogle Scholar
  124. 124.
    Zhao ZQ, Corvera JS, Halkos ME, Kerendi F, Wang NP, Guyton RA, Vinten-Johansen J (2003) Inhibition of myocardial injury by ischemic postconditioning during reperfusion: comparison with ischemic preconditioning. Am J Physiol Heart Circ Physiol 285:H579–H588. doi: 10.1152/ajpheart.01064.2002 PubMedCrossRefGoogle Scholar
  125. 125.
    Zhu H, Hou J, Roe JL, Park KH, Tan T, Zheng Y, Li L, Zhang C, Liu J, Liu Z, Ma J, Walters TJ (2015) Amelioration of ischemia–reperfusion induced muscle injury by the recombinant human MG53 protein. Muscle Nerve 52:852–858. doi: 10.1002/mus.24619 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Yang Yang
    • 1
    • 2
    • 3
  • Zhiqiang Ma
    • 4
  • Wei Hu
    • 2
  • Dongjin Wang
    • 3
  • Shuai Jiang
    • 5
  • Chongxi Fan
    • 4
  • Shouyin Di
    • 4
  • Dong Liu
    • 6
  • Yang Sun
    • 7
  • Wei Yi
    • 1
  1. 1.Department of Cardiovascular Surgery, Xijing HospitalThe Fourth Military Medical UniversityXi’anChina
  2. 2.Department of Biomedical EngineeringThe Fourth Military Medical UniversityXi’anChina
  3. 3.Department of Thoracic and Cardiovascular Surgery, Affiliated Drum Tower HospitalNanjing University Medical SchoolNanjingChina
  4. 4.Department of Thoracic Surgery, Tangdu HospitalThe Fourth Military Medical UniversityXi’anChina
  5. 5.Department of Aerospace MedicineThe Fourth Military Medical UniversityXi’anChina
  6. 6.State Key Laboratory of Cardiovascular Disease, Fuwai HospitalNational Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical CollegeBeijingChina
  7. 7.Department of Geriatrics, Xijing HospitalThe Fourth Military Medical UniversityXi’anChina

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