Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3

Tsutsumi, Yasuo M.; Tsutsumi, Rie; Horikawa, Yousuke T.; Shibata, Yoko; Hamaguchi, Eisuke; Kitahata, Hiroshi; Kasai, Asuka; Kambe, Noriko; Tanaka, Katsuya

doi:10.1007/s00540-014-1816-8

Cited by 7 publications

(6 citation statements)

References 38 publications

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“…Cav-3 is a major isoform of the caveolin family proteins to form cardiomyocyte caveolae [20], serving as a platform to enrich cardioprotective signaling molecules, including PI3K/Akt [53] and JAK/STAT [54]. It has been reported that both caveolae and caveolin-3 are critical for retaining myocardial tolerance to I/R injury [21, 55] and Cav-3 expression is also required for opioid induced cardioprotection [23]. Therefore, any alteration of Cav-3 expression in diabetes may be implicated in the compromised RPC-mediated cardioprotection, and thus, restoring Cav-3 expression should be beneficial to preserve the effectiveness of RPC in diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…Caveolin-3 (Cav-3), the dominant isoform in cardiac myocytes, is a determinant of caveolae formation [20]. Increasing evidences indicate that Cav-3 is necessary for the myocardium to retain tolerance to I/R injury [21, 22] and is required for opioid preconditioning to confer cardiac protection [23]. However, in diabetes, the cardiac Cav-3 expression is impaired by hyperglycemia-induced oxidative stress [24], accompanied with lower activation of Akt and STAT3 [25, 26], while the diabetic hearts are more vulnerable to I/R injury [25, 27] and less responsive to RPC [10, 15].…”

Section: Introductionmentioning

confidence: 99%

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Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling

Lei

Xia

et al. 2019

Oxidative Medicine and Cellular Longevity

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Diabetic hearts are more vulnerable to ischemia/reperfusion (I/R) injury and less responsive to remifentanil preconditioning (RPC), but the underlying mechanisms are incompletely understood. Caveolin-3 (Cav-3), the dominant isoform of cardiomyocyte caveolae, is reduced in diabetic hearts in which oxidative stress is increased. This study determined whether the compromised RPC in diabetes was an independent manifestation of hyperglycemia-induced oxidative stress or linked to impaired Cav-3 expression with associated signaling abnormality. RPC significantly attenuated postischemic infarction, cardiac dysfunction, myocardial apoptosis, and 15-F2t-isoprostane production (a specific marker of oxidative stress), accompanied with increased Cav-3 expression and enhanced Akt and STAT3 activation in control but not in diabetic rats. Pretreatment with the antioxidant N-acetylcysteine (NAC) attenuated hyperglycemia-induced reduction of Cav-3 expression and Akt and STAT3 activation and restored RPC-mediated cardioprotection in diabetes, which was abolished by cardiac-specific knockdown of Cav-3 by AAV9-shRNA-Cav-3, PI3K/Akt inhibitor wortmannin, or JAK2/STAT3 inhibitor AG490, respectively. Similarly, NAC could restore RPC protection from high glucose and hypoxia/reoxygenation-induced injury evidenced by decreased levels of LDH release, 15-F2t-isoprostane, O2-, and JC-1 monomeric cells, which were reversed by caveolae disrupter methyl-β-cyclodextrin, wortmannin, or AG490 in isolated primary cardiomyocytes or siRNAs of Cav-3, Akt, or STAT3 in H9C2 cells. Either methyl-β-cyclodextrin or Cav-3 knockdown reduced Akt and STAT3 activation. Further, the inhibition of Akt activation by a selective inhibitor or siRNA reduced STAT3 activation and vice versa, but they had no effects on Cav-3 expression. Thus, hyperglycemia-induced oxidative stress abrogates RPC cardioprotection by impairing Cav-3-modulated PI3K/Akt and JAK2/STAT3 signaling. Antioxidant treatment with NAC could restore RPC-induced cardioprotection in diabetes by improving Cav-3-dependent Akt and STAT3 activation and by facilitating the cross talk between PI3K/Akt and JAK2/STAT3 signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling

Lei

Xia

et al. 2019

Oxidative Medicine and Cellular Longevity

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“…Recent work has identified caveolae as signaling epicenters made up of essential scaffolding proteins called caveolins. Caveolae and caveolins are necessary for the precise temporal and spatial localization and organization of cellular signaling molecules [22, 38] involved in cardiac protection [21, 46, 55, 57, 58] and cardiac remodeling [20]. There are three distinct caveolin (Cav) isoforms including Cav-1 and Cav-2, which are ubiquitous in all cell types and Cav-3, which is found predominantly in skeletal and cardiac myocytes [11, 41, 52].…”

Section: Introductionmentioning

confidence: 99%

Electrophysiology and metabolism of caveolin-3-overexpressing mice

et al. 2016

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Caveolin-3 (Cav-3) plays a critical role in organizing signaling molecules and ion channels involved in cardiac conduction and metabolism. Mutations in Cav-3 are implicated in cardiac conduction abnormalities and myopathies. Additionally, cardiac specific overexpression of Cav-3 (Cav-3 OE) is protective against ischemic and hypertensive injury suggesting a potential role for Cav-3 in basal cardiac electrophysiology and metabolism involved in stress adaptation. We hypothesized that overexpression of Cav-3 may alter baseline cardiac conduction and metabolism. We examined: 1) ECG telemetry recordings at baseline and during pharmacological interventions, 2) ion channels involved in cardiac conduction with immunoblotting and computational modeling, and 3) baseline metabolism in Cav-3 OE and transgene negative littermate control mice. Cav-3 OE mice had decreased heart rates, prolonged PR intervals, and shortened QTc intervals with no difference in activity compared to control mice. Dobutamine or propranolol did not cause significant changes between experimental groups in maximal (dobutamine) or minimal (propranolol) heart rate. Cav-3 OE mice had an overall lower chronotropic response to atropine. Expression of Kv1.4 and Kv4.3 channels, Nav1.5 channels and connexin 43 were increased in Cav-3 OE mice. A computational model integrating the immunoblotting results indicated shortened action potential duration in Cav-3 OE mice linking the change in channel expression to the observed electrophysiology phenotype. Metabolic profiling showed no gross differences in VO2, VCO2, respiratory exchange ratio, and heat generation, feeding or drinking. In conclusion, Cav-3 OE mice have changes in ECG intervals, heart rates, and cardiac ion channel expression. These findings give novel mechanistic insights into previously reported Cav-3 dependent cardioprotection.

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“…These data suggest that GGA utilizes caveolae and caveolins to navigate the complex cell structure and facilitate cardioprotection by optimizing spatial and temporal signaling to mitochondria (Figure ). Several studies have also demonstrated that combined administration of GGA with isoflurane has a synergistic effect, enhancing protection against myocardial infarction to a greater extent than either drug alone, and that the protective effect is mediated by Cav‐3. Kitahata et al also observed that sevoflurane could enhance the cardioprotective effect of GGA, which HSP70 is involved in.…”

Section: Role Of Gga In Myocardial Irimentioning

confidence: 99%

“…Mediating the localization and activation of HSP70 63 ; optimizing spatial and temporal signaling to mitochondria 63,65 ; protecting mitochondrial function 57,63,65 HSP90 Protecting endothelial function by activating the HSP90-AMPK-eNOS-NO 46 and PI3 kinase-Akt-eNOS-NO pathways 49 Atrial fibrillation HSP72 Reducing AF inducibility by suppressing prolongation of APD and ERP and conduction slowing 76,77 HSP27 Preventing AF progression by suppressing ADP/ERP reduction and myolysis of the myocardium 21,84 Myocardial injury from HHS HSP70 Reducing cardiomyocyte apoptosis by increasing Bcl-2 expression and decreasing the release of cytochrome c from mitochondria 88 Psychologic stress HSP70 Reducing cardiomyocyte apoptosis by inhibiting activation of the Fas signaling pathway 89 Doxorubicin cardiac toxicity HSP90 Reducing oxidative stress in NOS-dependent and NOS-independent manners 49 Reducing cardiomyocyte apoptosis by blocking the proapoptotic RHO/ ROCK1 pathway 37 Insulin resistance HSP70/HSP72 Improving glucose homeostasis and insulin sensitivity 33,99,100 ; JNK inactivation in the liver 99 DMR HSP22, HSP27, HSP70 Reducing formation of amyloid oligomers and aggregates; reducing cardiomyocyte apoptosis by inhibiting the release of cytochrome c from mitochondria, and activation of caspase-3 76 Heart failure HSP22, HSP27 Protecting mitochondrial function 18 Endothelial inflammation HSP70 Inhibiting TNFα-induced upregulation of ECAMs 90…”

Section: Caveolin-3mentioning

confidence: 99%

Effects of geranylgeranylacetone upon cardiovascular diseases

Zeng

Wang

Chen

et al. 2018

Cardiovascular Therapeutics

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Heat shock proteins (HSPs) are an important family of protective proteins. They are involved actively in an array of cellular processes, including protective effects on the cardiovascular system in response to various stimuli. Increasing evidence shows that pharmacologic interventions that induce expression of HSPs may be a novel approach for the treatment of cardiovascular diseases. However, agents that induce expression of HSPs used previously are toxic or have harmful side effects, which limit their clinical application. Geranylgeranylacetone (GGA) is not only a widely used antiulcer agent in Asia, but also a nontoxic inducer of HSPs expression. It increases the expression of HSPs rapidly in the presence of ischemia, anoxia, oxidative stress, and toxicants, thereby having significant protective effects. The cardioprotective effects of GGA have been corroborated by experiments in vivo and in vitro. Importantly, several derivatives of GGA have been synthesized that have improved pharmaco-chemical and HSPs-boosting properties. In this review, the current knowledge and potential cardioprotective mechanisms of GGA are summarized comprehensively. We discuss the protective effects of GGA in cardiovascular diseases and myocardial injury induced by physical or chemical injury. Currently available information suggests that GGA could be employed as a novel pharmacologic intervention against cardiovascular disease.

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Geranylgeranylacetone and volatile anesthetic-induced cardiac protection synergism is dependent on caveolae and caveolin-3

Abstract: Combined administration of GGA + isoflurane had a synergistic effect, enhancing the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by Cav-3 expression.

Cited by 7 publications

References 38 publications

Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling

Hyperglycemia-Induced Oxidative Stress Abrogates Remifentanil Preconditioning-Mediated Cardioprotection in Diabetic Rats by Impairing Caveolin-3-Modulated PI3K/Akt and JAK2/STAT3 Signaling

Electrophysiology and metabolism of caveolin-3-overexpressing mice

Effects of geranylgeranylacetone upon cardiovascular diseases

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