Cardioprotective Role of Caveolae in Ischemia-Reperfusion Injury
Translational Medicine

Translational Medicine
Open Access

ISSN: 2161-1025

+44 1223 790975

Review Article - (2013) Volume 3, Issue 1

Cardioprotective Role of Caveolae in Ischemia-Reperfusion Injury

Junhui Sun1*, Tiffany Nguyen1, Mark J Kohr1,2, Sara Menazza1 and Elizabeth Murphy1
1Systems Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
2Department of Pathology, Johns Hopkins Medical Institutions, 720 Rutland Avenue, Baltimore, MD 21205, USA
*Corresponding Author: Junhui Sun, Systems Biology Center, National Heart Lung and Blood Institute, National Institutes of Health, 10 Center Drive, Bldg10/ Rm8N206, Bethesda, MD 20892, USA, Tel: 301-496-8192, Fax: 301-402-0190 Email:


Caveolae are flask-like invaginations of the plasma membrane enriched in cholesterol, sphingolipids, the marker protein caveolin and the coat protein cavin. In cardiomyocytes, multiple signaling molecules are concentrated and organized within the caveolae to mediate signaling transduction. Recent studies suggest that caveolae and caveolaeassociated signaling molecules play an important role in protecting the myocardium against ischemia-reperfusion injury. For example, cardiac-specific overexpression of caveolin-3 has been shown to lead to protection that mimics ischemic preconditioning, while the knockout of caveolin-3 abolished ischemic preconditioning. In this review, we discuss the molecular mechanisms and signaling pathways that are involved in caveolae-mediated cardioprotection, and examine the potential for caveolae as a therapeutic target for pharmaceutical intervention to treat cardiovascular disease.



Ischemia-reperfusion (I/R)-induced myocardial cell death is a major cause of morbidity and mortality in heart disease. Ischemia leads to ATP depletion and a rise in intracellular calcium (Ca2+), which induces mitochondrial Ca2+ accumulation. The duration of ischemia is a critical factor in determining ischemic injury and cell fate. Although the reintroduction of oxygen upon reperfusion allows for ATP production to resume, there is a burst of reactive oxygen species (ROS) that occurs because of damage to electron transport chain components and mitochondrial Ca2+ overload. This triggers the opening of the mitochondrial permeability transition pore and further compromises myocardial energetics. Therefore, mitochondria are thought to be a central player or end effector in cell death, and many cardioprotective signaling mechanisms have been found to converge on the mitochondria and reduce cell death [1,2]. The cardioprotective strategies of ischemic preconditioning (IPC) and postconditioning (PostC) have important clinical implications. Compared to the early use of IPC, which is only practical to perform in patients undergoing coronary artery bypass grafting, PostC is more clinically relevant but there is a very narrow window for such an intervention. Although the ischemic myocardium can be salvaged via myocardial reperfusion, irreversible injury also occurs during reperfusion. The most likely cause of myocyte death during I/R injury is the disruption of cellular membranes and the loss of sarcolemmal integrity [3]. There are many components involved in cardioprotection; however, there is uncertainty as to how signaling networks interact together to confer protection. In particular, further studies are needed to explore how the signaling molecules interact and translocate to the mitochondria.

Caveolae are flask-like invaginations [4,5] that create signaling microdomains of the plasma membrane enriched with cholesterol, sphingolipids, the marker protein caveolin, and the coat protein cavin [6,7]. Caveolins have three isoforms (caveolin 1-3) and cavins consist of four isoforms (cavin 1-4). Caveolin-3 [8] and cavin-4 [9] are expressed predominantly in cardiac muscle and have been identified as important proteins involved in cardiomyopathy [10,11]. In cardiomyocytes, there are many different signaling molecules that are concentrated and organized within the caveolae, and these can mediate signal transduction [12,13]. Recent studies suggest that caveolae and caveolae-associated signaling molecules plays an important role in protecting the myocardium against I/R injury [11,14]. For example, the cardiac-specific over-expression of caveolin-3 led to myocardial protection that mimicked IPC [15] and also attenuated cardiac hypertrophy [16]. Conversely, the knockout of caveolin-3 [15] or disruption of caveolae via cholesterol sequestration, abolished IPCinduced protection [17,18]. Caveolae could provide critical protection by directly sensing extracellular stress, such as ischemia or flowinduced mechanical stretch, and elicit multiple signaling pathways in order to mediate effective protection. These pathways could result in mitochondrial signaling, alteration in substrate uptake, the sensing of mechanical stretch, and/or reparation of damaged membranes.

Caveolae-Associated Cardioprotective Signaling

Multiple signaling molecules such as G-protein-coupled receptors (GPCRs), ion channels and transporters, and other important signaling molecules, are concentrated and organized within the caveolae in cardiomyocytes, producing a unique and homeostatic pH, ionic, and redox microenvironment [13,19,20]. For example, endothelial nitric oxide (NO) synthase (eNOS) [21] and NADPH oxygenase (NOX) [22] are localized in caveolae/lipid rafts. The compartmentalized generation of NO (by eNOS) and superoxide (by NOX and/or uncoupled eNOS) might have a dramatic impact on oxidative/nitrosative stress during I/R injury. Therefore, the concerted or disturbed regulation of these redox systems plays important roles in physiology and disease [23]. Acute stress, as occurs with I/R, can cause a dramatic change within caveolae, thus allowing these membrane invaginations to serve as essential sensors for eliciting downstream signaling cascades.

The activation of a number of GPCRs by molecules such as adenosine, bradykinin, catecholamines, and opioids that are released by the myocardium during IPC or PostC has been found to be protective [24-26]. Recently, we found that activation of the extracellular calcium sensing receptor (CaSR), which is a GPCR that is expressed in cardiomyocytes and is predominantly localized to the caveolae, plays an important role in mediating IPC-induced cardioprotection [27]. Interestingly, activation of many GPCRs has been found to mimic the cardioprotective effects of IPC or PostC. However, often the effects of activating multiple GPCRs is not additive [26,28]. One possible explanation could be that activation of any of these GPCRs leads to caveolae-mediated vesicle internalization, which subsequently leads to a decrease in GPCR sensitivity in cardiomyocytes. In addition, activation of some of GPCRs may result in the activation of the same downstream signaling pathways, such as the PI3K/Akt/eNOS pathway [29]. However, studies have yet to determine whether there is sequential activation and/or interaction among different caveolaelocalized receptor-mediated signaling pathways.

Caveolae-Mediated Translocation of Protective Signaling to Mitochondria

Mitochondria have been recognized as the end effector of cardioprotective interventions such as IPC and PostC [30,31]. Caveolaemediated endocytosis has been suggested to result in the formation of a signalasome which is thought to target mitochondria [32,33]. In our recent studies, we have found that IPC leads to the translocation of caveolin-3-associated eNOS to mitochondria, and this is associated with an increase in the S-nitrosylation (SNO) of mitochondrial proteins. Disruption of caveolae via cholesterol sequestering agents (i.e., methyl- β-cyclodextrin), abolished the mitochondrial translocation of eNOS and blocked the increase in SNO proteins and protection induced by IPC [18]. Interestingly, two populations of mitochondria, i.e., subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM), are distributed in cardiomyocytes according to their subcellular localization. Given the close proximity of SSM to caveolae, it is possible that caveolae-mediated cardioprotective signaling may preferentially target to SSM rather than IFM. Since the energetics of SSM might play an important role in regulation of ionic homeostasis and thus plasma membrane integrity, the modulation of this population of mitochondria should be crucial for cardioprotection.

Substrate Uptake and Transportation

On a beat-to-beat basis, the heart has a high energetic demand that is necessary to support contractile function, ionic homeostasis, and metabolic processes. Under normal conditions, cardiomyocytes primarily use fatty acids and glucose to generate ATP via mitochondrial oxidative phosphorylation [34-36]. There is a shift in substrate preference towards glucose utilization during the development of cardiac hypertrophy, which may worsen if the hypertrophic myocardium transitions into heart failure [34,35,37]. Fatty acid and glucose uptake in the myocardium are facilitated by families of fatty acid transporters (FAT) and glucose transporters (GLUT). In cardiomyocytes, the most important FAT is fatty acid translocase, also known as CD36. This transporter is present in both plasma and microsomal fractions, and insulin does not affect the cellular distribution [38]. In mouse embryonic fibroblasts, caveolin-1 has been found to be required for CD36 localization and function at the plasma membrane [39]. However, a recent study showed normal expression and function for CD36 in caveolin-3-/- mouse hearts, suggesting that in cardiomyocytes, CD36-mediated fatty acid uptake is not dependent on caveolin-3 or caveolae [40].

Basal glucose uptake in cardiomyocytes is mediated by GLUT1, while increased work load or insulin stimuli leads to the plasma membrane translocation of GLUT4 and the enhancement of glucose uptake [37]. Although the uptake and oxidation of fatty acids and glucose were normal in caveolin-3-/- mice [40], recent studies suggest that caveolae may also play an important role as metabolic platforms [19,41]. Horikawa et al. have shown that anesthetic preconditioning is dependent on the presence of caveolae and the expression of caveolin-3 [42]. Tsutsumi et al. used an in vivo I/R model to test anesthetic preconditioning in wild-type, caveolin-1-/-, and caveolin-3-/- mice and found that wild-type and caveolin-1-/- mice could be protected, while caveolin-3-/- mice in which caveolae are totally lost in cardiomyocytes, could not be protected. Further, they found that delayed anesthetic preconditioning appears to be associated with the specific up-regulation and co-localization of GLUT-4 with caveolin-3 [41]. Myocardial ischemia is reported to stimulate glucose uptake via GLUT-4 translocation from intracellular vesicles to the sarcolemma. Koneru et al. found that there was a significant role for the Akt/eNOS/ Cav-3 signaling pathway in mediating the sarcolemmal translocation of GLUT-4 in the IPC heart, thus leading to myocardial protection [43]. In addition, the IPC-induced Akt/eNOS/Cav-3-mediated GLUT- 4 translocation to the sarcolemma could be abolished with the use of a reducing agent, suggesting a potential role for redox-dependent signaling (i.e., NO-mediated protein S-nitrosylation).

Mechanical Stress Sensing and Membrane Repair

Mechanical or shear stress has been found to induce caveolae formation and the activation of extracellular signal-regulated kinase (ERK) in vascular endothelial cells [44,45], and caveolae function as a mechanotransduction sensor in the cardiovascular system [46]. Kozera et al. showed that in cardiomyocytes, caveolae provide a means of buffering changes in membrane tension [47]. A recent study from Sinha et al. found that acute mechanical stress induced by stretching or osmotic swelling led to the rapid disassembly and disappearance of caveolae, while reducing mechanical stress results in caveolae reassembly [48]. Direct evidence for the sensing of mechanical stress by caveolae comes from a recent study which showed that myotubes from muscular dystrophic patients have enhanced membrane fragility under mechanical stress in which there is an absence of functional caveolae reservoirs [48]. The mechanical stretch-induced disassembly of caveolae and redistribution of glycosphingolipids may be an important cellular adaptation to mechanical stretch [49]. Thus, during cell stretch or swelling, as occurs during I/R, caveolar membranes may serve as critical plasma membrane components that could be incorporated into the sarcolemmal surface to maintain membrane integrity.

Besides sensing mechanical stress in the plasma membrane, caveolins are also involved in the regulation of membrane repair. Mutations in caveolin-3 and the muscle repair protein dysferlin are linked to muscular dystrophy, and caveolin-3 has been found to cause the surface retention of dysferlin and regulate endocytosis of the muscle repair protein dysferlin [50]. Recent studies from Dr. Ma’s group have discovered that a muscle-specific TRIM family protein (TRIM72), also named as mitsugumin 53 (MG53), interacts with caveolin-3 and dysferlin to regulate membrane repair in striated muscle [51-53]. Cao et al. found that I/R causes the down-regulation of MG53, which could be prevented by IPC [54]. In addition, MG53 deficiency increases myocardial vulnerability to I/R injury and abolishes IPC-induced protection. The cardioprotective effects of MG53 are attributable to the MG53-dependent interaction of caveolin-3 with PI3K and the subsequent activation of the reperfusion injury salvage kinase pathway [54]. In another study, Wang et al. found that ablation of MG53 prevents membrane repair and exacerbates mitochondrial dysfunction and the loss of cardiomyocytes during I/R injury [55]. Interestingly, MG53-dependent membrane repair is mediated by a cholesteroldependent mechanism, which may also be related to the trafficking of caveolae [55].

Change of Caveolae in Aged and Diseased Hearts

Myocardial IPC represents one of the most powerful endogenous protective mechanisms against I/R injury. IPC-induced cardioprotection seems to be reduced with aging, both in experimental [56-58] and clinical studies [59,60]. Recent studies also suggest that PostCinduced cardioprotection is lost in aged animals [58,61]. Alterations to intracellular myocardial ultrastructure and signaling pathways may be responsible for this age-related decline in cardioprotection. Emerging data suggest that caveolae play important role(s) in cardioprotection [14,16,18,41], and caveolin-3-/- mice have been shown to develop a progressive cardiomyopathic phenotype [62]. The dissociation of caveolin from caveolae has also been found to be associated with aging and heart failure [63]. During early adulthood in mice (four months), caveolin-3-/- hearts display significant hypertrophy, dilation, and reduced fractional shortening. A recent study demonstrated that there is a selective decrease in the expression of caveolin-3 in murine models of heart failure, and in failing human hearts, there is a direct correlation between the levels of caveolin-3 and other markers of the heart failure phenotype [64]. Thus, a decrease or the loss of caveolin-3/caveolae has the potential to lead to a loss of cardioprotection and the development of heart disease during aging [65,66].

Therapeutic Prospective

In muscle, mutation and deficiency in the caveolin-3 gene lead to various caveolinmyopathies and one mutation in caveolin-3 has been reported to be the cause of hypertrophic cardiomyopathy. A recent study by Horikawa et al. showed that cardiac-specific over-expression of caveolin-3 via adenovirus, attenuates cardiac hypertrophy [11]. This provides a promising result for the use of caveolin-3 as a therapeutic target in the heart. In addition, an early study by Young et al. showed that perfusion with a caveolin-1 peptide from the scaffolding region, led to vascular dilation via enhanced release of endothelium-derived NO, and significantly attenuated post-I/R-induced cardiac contractile dysfunction in isolated perfused rat hearts [67]. Given our recent study suggesting that caveolae may transduce signaling via the eNOS/NO/ SNO pathway in IPC hearts, it would be interesting to test whether perfusion with a caveolin-3 mimic peptide from the scaffolding region could also elicit protective effects in I/R hearts [68].

Lipid composition is important for the structure and function of caveolae. Disruption of caveolae by cholesterol-depleting agents, such as cyclodextrin, has been routinely applied in cell and animal studies. Statins, which are widely used as lipid-lowering drugs, have been also used in the prevention and treatment of coronary artery disease because of their ability to increase NO bioavailability, improve endothelial function, and enhance antioxidant and anti-inflammatory effects. A recent clinical study showed that perioperative simvastatin therapy significantly reduced myocardial injury and inflammation in patients undergoing noncoronary artery surgery by activating eNOS with an increase in Hsp90 expression and a decrease in caveolin-1 expression. Simvastatin has cardioprotective effects that are independent from its ability to reduce lipid levels and mainly relies on changes in caveolin and caveolin-associated signaling molecules. This suggests that therapeutic interventions that seek to modify caveolae/caveolin levels may be promising for treating ischemic diseases. In addition, Oshikawa et al. showed that extracellular superoxide dismutase (ecSOD) localized at caveolae catalyzes the dismutation of superoxide to H2O2, which is essential for the full activation of VEGF signaling and the promotion of angiogenesis after ischemia. Thus, caveolae could also serve as a potential therapeutic target for angiogenesis-dependent cardiovascular disease [69].

Although caveolae are found in almost all mammalian cell types, endothelial cells usually show a higher level of caveolae and this reflects the physiological role of caveolae in these cell types (i.e., engage in vesicular traffic for uptake, internalization and transportation of molecules). The monolayer of endothelial cells lining vessel walls forms a size-selective and semipermeable barrier which controls the movement of fluid between the blood and interstitial tissues, thus allowing for the potential exploitation of caveolae-mediated delivery systems for cardioprotective nano-compounds and an exciting therapeutic prospective.

In conclusion, caveolin-3 and caveolae play important protective roles in the myocardium by regulating GPCR-coupled kinase signaling pathways, changing the activity of ionic or substrate channels/ transporters, activating and translocating specific caveolae-associated signaling molecules, and sensing mechanical stress and initiating plasma membrane repair (Figure 1). As a result, emerging data suggest that caveolae may be an effective therapeutic target for the treatment of myocardial ischemia and caveolae-related cardiomyopathies [70].


Figure 1: Cardioprotective role of caveolae in I/R injury. Caveloae can potentially sense and respond to myocardial I/R stress by (1) initiating various GPCRcoupled kinase signaling pathways; (2) changing the activities of ionic or substrate channels/transporters (“O”); (3) activating and translocating specific caveolaeassociated signaling molecules (“N”), such as eNOS; and (4) sensing mechanical stress and initiating plasma membrane repair (“M”).


This work was supported by the National Heart Lung and Blood Institute Intramural Research Program.


  1. Murphy E, Steenbergen C (2008) Mechanisms underlying acute protection from cardiac ischemia-reperfusion injury. Physiol Rev 88: 581-609.
  2. Murphy E, Steenbergen C (2011) What makes the mitochondria a killer? Can we condition them to be less destructive? Biochim Biophys Acta 1813: 1302-1308.
  3. Jennings RB (2013) Historical perspective on the pathology of myocardial ischemia/reperfusion injury. Circ Res 113: 428-438.
  4. Palade G (1953) Fine structure of blood capillaries. J Appl Physics 24: 1424-1436.
  5. YAMADA E (1955) The fine structure of the gall bladder epithelium of the mouse. J Biophys Biochem Cytol 1: 445-458.
  6. Galbiati F, Razani B, Lisanti MP (2001) Emerging themes in lipid rafts and caveolae. Cell 106: 403-411.
  7. Hansen CG, Nichols BJ (2010) Exploring the caves: cavins, caveolins and caveolae. Trends Cell Biol 20: 177-186.
  8. Song KS, Scherer PE, Tang Z, Okamoto T, Li S, et al. (1996) Expression of caveolin-3 in skeletal, cardiac, and smooth muscle cells. Caveolin-3 is a component of the sarcolemma and co-fractionates with dystrophin and dystrophin-associated glycoproteins. J Biol Chem 271: 15160-15165.
  9. Ogata T, Ueyama T, Isodono K, Tagawa M, Takehara N, et al. (2008) MURC, a muscle-restricted coiled-coil protein that modulates the Rho/ROCK pathway, induces cardiac dysfunction and conduction disturbance. Mol Cell Biol 28: 3424-3436.
  10. Chidlow JH Jr, Sessa WC (2010) Caveolae, caveolins, and cavins: complex control of cellular signalling and inflammation. Cardiovasc Res 86: 219-225.
  11. Sellers SL, Trane AE, Bernatchez PN (2012) Caveolin as a potential drug target for cardiovascular protection. Front Physiol 3: 280.
  12. Insel PA, Head BP, Ostrom RS, Patel HH, Swaney JS, et al. (2005) Caveolae and lipid rafts: G protein-coupled receptor signaling microdomains in cardiac myocytes. Ann N Y Acad Sci 1047: 166-172.
  13. Harvey RD, Calaghan SC (2012) Caveolae create local signalling domains through their distinct protein content, lipid profile and morphology. J Mol Cell Cardiol 52: 366-375.
  14. Roth DM, Patel HH (2011) Role of caveolae in cardiac protection. Pediatr Cardiol 32: 329-333.
  15. Tsutsumi YM, Horikawa YT, Jennings MM, Kidd MW, Niesman IR, et al. (2008) Cardiac-specific overexpression of caveolin-3 induces endogenous cardiac protection by mimicking ischemic preconditioning. Circulation 118: 1979-1988.
  16. Horikawa YT, Panneerselvam M, Kawaraguchi Y, Tsutsumi YM, Ali SS, et al. (2011) Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling. J Am Coll Cardiol 57: 2273-2283.
  17. Das M, Gherghiceanu M, Lekli I, Mukherjee S, Popescu LM, et al. (2008) Essential role of lipid raft in ischemic preconditioning. Cell Physiol Biochem 21: 325-334.
  18. Sun J, Kohr MJ, Nguyen T, Aponte AM, Connelly PS, et al. (2012) Disruption of caveolae blocks ischemic preconditioning-mediated S-nitrosylation of mitochondrial proteins. Antioxid Redox Signal 16: 45-56.
  19. Ortegren U, Aboulaich N, Ost A, Strålfors P (2007) A new role for caveolae as metabolic platforms. Trends Endocrinol Metab 18: 344-349.
  20. Balijepalli RC, Kamp TJ (2008) Caveolae, ion channels and cardiac arrhythmias. Prog Biophys Mol Biol 98: 149-160.
  21. Feron O, Belhhassen L, Kobzik L, Smith TW, Kelly RA, et al. (1996) Endothelial nitric oxide synthase targeting to caveolae. Specific interactions with caveolin isoforms in cardiac myocytes and endothelial cells. J Biol Chem 271: 22810-22814.
  22. Hilenski LL, Clempus RE, Quinn MT, Lambeth JD, Griendling KK (2004) Distinct subcellular localizations of Nox1 and Nox4 in vascular smooth muscle cells. Arterioscler Thromb Vasc Biol 24: 677-683.
  23. Patel HH, Insel PA (2009) Lipid rafts and caveolae and their role in compartmentation of redox signaling. Antioxid Redox Signal 11: 1357-1372.
  24. Kloner RA, Rezkalla SH (2006) Preconditioning, postconditioning and their application to clinical cardiology. Cardiovasc Res 70: 297-307.
  25. Sanada S, Komuro I, Kitakaze M (2011) Pathophysiology of myocardial reperfusion injury: preconditioning, postconditioning, and translational aspects of protective measures. Am J Physiol Heart Circ Physiol 301: H1723-1741.
  26. Hausenloy DJ, Yellon DM (2007) Preconditioning and postconditioning: united at reperfusion. Pharmacol Ther 116: 173-191.
  27. Sun J, Murphy E (2010) Calcium-sensing receptor: a sensor and mediator of ischemic preconditioning in the heart. Am J Physiol Heart Circ Physiol 299: H1309-1317.
  28. Downey JM, Krieg T, Cohen MV (2008) Mapping preconditioning's signaling pathways: an engineering approach. Ann N Y Acad Sci 1123: 187-196.
  29. Tsang A, Hausenloy DJ, Mocanu MM, Yellon DM (2004) Postconditioning: a form of "modified reperfusion" protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res 95: 230-232.
  30. Hausenloy DJ, Ong SB, Yellon DM (2009) The mitochondrial permeability transition pore as a target for preconditioning and postconditioning. Basic Res Cardiol 104: 189-202.
  31. Murphy E, Steenbergen C (2007) Preconditioning: the mitochondrial connection. Annu Rev Physiol 69: 51-67.
  32. Garlid KD, Costa AD, Quinlan CL, Pierre SV, Dos Santos P (2009) Cardioprotective signaling to mitochondria. J Mol Cell Cardiol 46: 858-866.
  33. Quinlan CL, Costa AD, Costa CL, Pierre SV, Dos Santos P, et al. (2008) Conditioning the heart induces formation of signalosomes that interact with mitochondria to open mitoKATP channels. Am J Physiol Heart Circ Physiol 295: H953-953H961.
  34. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90: 207-258.
  35. Schwenk RW, Luiken JJ, Bonen A, Glatz JF (2008) Regulation of sarcolemmal glucose and fatty acid transporters in cardiac disease. Cardiovasc Res 79: 249-258.
  36. Glatz JF, Bonen A, Ouwens DM, Luiken JJ (2006) Regulation of sarcolemmal transport of substrates in the healthy and diseased heart. Cardiovasc Drugs Ther 20: 471-476.
  37. Steinbusch LK, Schwenk RW, Ouwens DM, Diamant M, Glatz JF, et al. (2011) Subcellular trafficking of the substrate transporters GLUT4 and CD36 in cardiomyocytes. Cell Mol Life Sci 68: 2525-2538.
  38. Müller H, Deckers K, Eckel J (2002) The fatty acid translocase (FAT)/CD36 and the glucose transporter GLUT4 are localized in different cellular compartments in rat cardiac muscle. Biochem Biophys Res Commun 293: 665-669.
  39. Ring A, Le Lay S, Pohl J, Verkade P, Stremmel W (2006) Caveolin-1 is required for fatty acid translocase (FAT/CD36) localization and function at the plasma membrane of mouse embryonic fibroblasts. Biochim Biophys Acta 1761: 416-423.
  40. Augustus AS, Buchanan J, Addya S, Rengo G, Pestell RG, et al. (2008) Substrate uptake and metabolism are preserved in hypertrophic caveolin-3 knockout hearts. Am J Physiol Heart Circ Physiol 295: H657-666.
  41. Tsutsumi YM, Kawaraguchi Y, Horikawa YT, Niesman IR, Kidd MW, et al. (2010) Role of caveolin-3 and glucose transporter-4 in isoflurane-induced delayed cardiac protection. Anesthesiology 112: 1136-1145.
  42. Horikawa YT, Patel HH, Tsutsumi YM, Jennings MM, Kidd MW, et al. (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.
  43. Koneru S, Penumathsa SV, Thirunavukkarasu M, Samuel SM, Zhan L, et al. (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: H2060-2072.
  44. Park H, Go YM, Darji R, Choi JW, Lisanti MP, et al. (2000) Caveolin-1 regulates shear stress-dependent activation of extracellular signal-regulated kinase. Am J Physiol Heart Circ Physiol 278: H1285-1293.
  45. Boyd NL, Park H, Yi H, Boo YC, Sorescu GP, et al. (2003) Chronic shear induces caveolae formation and alters ERK and Akt responses in endothelial cells. Am J Physiol Heart Circ Physiol 285: H1113-1122.
  46. Yu J, Bergaya S, Murata T, Alp IF, Bauer MP, et al. (2006) Direct evidence for the role of caveolin-1 and caveolae in mechanotransduction and remodeling of blood vessels. J Clin Invest 116: 1284-1291.
  47. Kozera L, White E, Calaghan S (2009) Caveolae act as membrane reserves which limit mechanosensitive I(Cl,swell) channel activation during swelling in the rat ventricular myocyte. PLoS One 4: e8312.
  48. Sinha B, Köster D, Ruez R, Gonnord P, Bastiani M, et al. (2011) Cells respond to mechanical stress by rapid disassembly of caveolae. Cell 144: 402-413.
  49. Gervásio OL, Phillips WD, Cole L, Allen DG (2011) Caveolae respond to cell stretch and contribute to stretch-induced signaling. J Cell Sci 124: 3581-3590.
  50. Hernández-Deviez DJ, Howes MT, Laval SH, Bushby K, Hancock JF, et al. (2008) Caveolin regulates endocytosis of the muscle repair protein, dysferlin. J Biol Chem 283: 6476-6488.
  51. Cai C, Masumiya H, Weisleder N, Matsuda N, Nishi M, et al. (2009) MG53 nucleates assembly of cell membrane repair machinery. Nat Cell Biol 11: 56-64.
  52. Cai C, Weisleder N, Ko JK, Komazaki S, Sunada Y, et al. (2009) Membrane repair defects in muscular dystrophy are linked to altered interaction between MG53, caveolin-3, and dysferlin. J Biol Chem 284: 15894-15902.
  53. Cai C, Masumiya H, Weisleder N, Pan Z, Nishi M, et al. (2009) MG53 regulates membrane budding and exocytosis in muscle cells. J Biol Chem 284: 3314-3322.
  54. Cao CM, Zhang Y, Weisleder N, Ferrante C, Wang X, et al. (2010) MG53 constitutes a primary determinant of cardiac ischemic preconditioning. Circulation 121: 2565-2574.
  55. Wang X, Xie W, Zhang Y, Lin P, Han L, et al. (2010) Cardioprotection of ischemia/reperfusion injury by cholesterol-dependent MG53-mediated membrane repair. Circ Res 107: 76-83.
  56. Turcato S, Turnbull L, Wang GY, Honbo N, Simpson PC, et al. (2006) Ischemic preconditioning depends on age and gender. Basic Res Cardiol 101: 235-243.
  57. Boengler K, Konietzka I, Buechert A, Heinen Y, Garcia-Dorado D, et al. (2007) Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol 292: H1764-1769.
  58. Boengler K, Buechert A, Heinen Y, Roeskes C, Hilfiker-Kleiner D, et al. (2008) Cardioprotection by ischemic postconditioning is lost in aged and STAT3-deficient mice. Circ Res 102: 131-135.
  59. Boengler K, Schulz R, Heusch G (2009) Loss of cardioprotection with ageing. Cardiovasc Res 83: 247-261.
  60. Abete P, Cacciatore F, Testa G, Della-Morte D, Galizia G, et al. (2010) Ischemic preconditioning in the aging heart: from bench to bedside. Ageing Res Rev 9: 153-162.
  61. Somers SJ, Lacerda L, Opie L, Lecour S (2011) Age, genetic characteristics and number of cycles are critical factors to consider for successful protection of the murine heart with postconditioning. Physiol Res 60: 971-974.
  62. Woodman SE, Park DS, Cohen AW, Cheung MW, Chandra M, et al. (2002) Caveolin-3 knock-out mice develop a progressive cardiomyopathy and show hyperactivation of the p42/44 MAPK cascade. J Biol Chem 277: 38988-38997.
  63. Ratajczak P, Damy T, Heymes C, Oliviéro P, Marotte F, et al. (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.
  64. Feiner EC, Chung P, Jasmin JF, Zhang J, Whitaker-Menezes D, et al. (2011) Left ventricular dysfunction in murine models of heart failure and in failing human heart is associated with a selective decrease in the expression of caveolin-3. J Card Fail 17: 253-263.
  65. 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.
  66. Hayashi T, Arimura T, Ueda K, Shibata H, Hohda S, et al. (2004) Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy. Biochem Biophys Res Commun 313: 178-184.
  67. 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: H2489-2495.
  68. Almansob MAS, Xu B, Zhou L, Hu X-X, Chen W, et al. (2012) Simvastatin reduces myocardial injury undergoing noncoronary artery cardiac surgery: a randomized controlled trial. Arterioscler Thromb Vasc Biol 32: 2304-2313.
  69. Oshikawa J, Urao N, Kim HW, Kaplan N, Razvi M, et al. (2010) Extracellular SOD-derived H2O2 promotes VEGF signaling in caveolae/lipid rafts and post-ischemic angiogenesis in mice. PLoS One 5: e10189.
  70. Wang Z, Tiruppathi C, Cho J, Minshall RD, Malik AB (2011) Delivery of nanoparticle: complexed drugs across the vascular endothelial barrier via caveolae. IUBMB Life 63: 659-667.
Citation: Sun J, Nguyen T, Kohr MJ, Menazza S, Murphy E (2013) Cardioprotective Role of Caveolae in Ischemia-Reperfusion Injury. Transl Med 3: 114.

Copyright: © 2013 Sun J, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.