Mechanical Stretch-Induced Protection against Myocardial Ischemia-Reperfusion Injury Involves AMP-Activated Protein Kinase

Jia, Hao; Kim, Hun-Sik; Choi, Woong; Ha, Tae Sun; Ahn, Hee-Yul; Kim, Chan-Hyung

doi:10.4196/kjpp.2010.14.1.1

Cited by 15 publications

(10 citation statements)

References 36 publications

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“…We next sought to determine the mechanosensitive signaling pathway that couples dystrophin to stretchinduced activation of nNOS. AMP-activated protein kinase (AMPK) phosphorylates nNOS-serine 1412 in multiple cell types, including skeletal muscle (40)(41)(42)(43), and can be activated by mechanical stimulation of cardiac muscle (44,45). Therefore, we investigated the involvement of AMPK in dystrophin-dependent mechano-nNOS signaling in cardiomyocytes.…”

Section: Stretch-induced Nnos Phosphorylation Is Impaired In Dystrophin-mentioning

confidence: 99%

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Garbincius

Michele

2015

Proc. Natl. Acad. Sci. U.S.A.

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Patients deficient in dystrophin, a protein that links the cytoskeleton to the extracellular matrix via the dystrophin-glycoprotein complex (DGC), exhibit muscular dystrophy, cardiomyopathy, and impaired muscle nitric oxide (NO) production. We used live-cell NO imaging and in vitro cyclic stretch of isolated adult mouse cardiomyocytes as a model system to investigate if and how the DGC directly regulates the mechanical activation of muscle NO signaling. Acute activation of NO synthesis by mechanical stretch was impaired in dystrophin-deficient mdx cardiomyocytes, accompanied by loss of stretch-induced neuronal NO synthase (nNOS) S1412 phosphorylation. Intriguingly, stretch induced the acute activation of AMP-activated protein kinase (AMPK) in normal cardiomyocytes but not in mdx cardiomyocytes, and specific inhibition of AMPK was sufficient to attenuate mechanoactivation of NO production. Therefore, we tested whether direct pharmacologic activation of AMPK could bypass defective mechanical signaling to restore nNOS activity in dystrophin-deficient cardiomyocytes. Indeed, activation of AMPK with 5-aminoimidazole-4-carboxamide riboside or salicylate increased nNOS S1412 phosphorylation and was sufficient to enhance NO production in mdx cardiomyocytes. We conclude that the DGC promotes the mechanical activation of cardiac nNOS by acting as a mechanosensor to regulate AMPK activity, and that pharmacologic AMPK activation may be a suitable therapeutic strategy for restoring nNOS activity in dystrophin-deficient hearts and muscle.T he muscular dystrophies are a group of muscle wasting disorders characterized by progressive weakening and degeneration of striated muscle. The most common form is Duchenne muscular dystrophy (DMD), an X-linked disorder caused by genetic disruption of dystrophin (1) that affects 1 in 3,500-5,000 males (2, 3). DMD and several other types of muscular dystrophy result from disruption of the dystrophin-glycoprotein complex (DGC), a structure that spans the sarcolemma and forms a mechanical linkage between the cytoskeleton and the extracellular matrix via the association of dystrophin with subsarcolemmal γ-actin and the binding of α-dystroglycan to laminin (4). The generally accepted role for this complex is to act as a molecular shock absorber and stabilize the plasma membrane during muscle contraction. Disruption of the DGC's linkage between the cytoskeleton and extracellular matrix, such as occurs in DMD (1, 5-7) or with the disruption of α-dystroglycan-laminin binding in glycosylation-deficient muscular dystrophies (8, 9), leads to destabilization of the plasma membrane, rendering skeletal muscle fibers and cardiomyocytes susceptible to stretch-or contraction-induced injury and cell death (10)(11)(12)(13)(14).In addition to this structural role, a signaling function for the DGC has been proposed based on its association with several signaling proteins including Grb2-Sos1 (15), MEK and ERK (16), heterotrimeric G protein subunits (17, 18), archvillin (19), and neuronal nitric oxide synthase (n...

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Section: Stretch-induced Nnos Phosphorylation Is Impaired In Dystrophin-mentioning

confidence: 99%

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Garbincius

Michele

2015

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, a previous study has suggested that stretch-activated ion channels also play a key role in cardiac pathophysiology [42] , and GdCl 3 is the most widely used antagonist of this channel. Abnormal tissue stretch is a classical feature of myocardial I/R [21,43] . Therefore, the antagonism effect of GdCl 3 on stretchactivated ion channels may also reflect another advantage of GdCl 3 over other drugs.…”

Section: Discussionmentioning

confidence: 99%

Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats

et al. 2016

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Aim:We have shown that low-dose gadolinium chloride (GdCl 3 ) abolishes arachidonic acid (AA)-induced increase of cytoplasmic Ca 2+ , which is known to play a crucial role in myocardial ischemia/reperfusion (I/R) injury. The present study sought to determine whether low-dose GdCl 3 pretreatment protected rat myocardium against I/R injury in vitro and in vivo. Methods: Cultured neonatal rat ventricular myocytes (NRVMs) were treated with GdCl 3 or nifedipine, followed by exposure to anoxia/ reoxygenation (A/R). Cell apoptosis was detected; the levels of related signaling molecules were assessed. SD rats were intravenously injected with GdCl 3 or nifedipine. Thirty min after the administration the rats were subjected to LAD coronary artery ligation followed by reperfusion. Infarction size, the release of serum myocardial injury markers and AA were measured; cell apoptosis and related molecules were assessed. Results: In A/R-treated NRVMs, pretreatment with GdCl 3 (2.5, 5, 10 μmol/L) dose-dependently inhibited caspase-3 activation, death receptor-related molecules DR5/Fas/FADD/caspase-8 expression, cytochrome c release, AA release and sustained cytoplasmic Ca 2+ increases induced by exogenous AA. In I/R-treated rats, pre-administration of GdCl 3 (10 mg/kg) significantly reduced the infarct size, and the serum levels of CK-MB, cardiac troponin-I, LDH and AA. Pre-administration of GdCl 3 also significantly decreased the number of apoptotic cells, caspase-3 activity, death receptor-related molecules (DR5/Fas/FADD) expression and cytochrome c release in heart tissues. The positive control drug nifedipine produced comparable cardioprotective effects in vitro and in vivo. Conclusion: Pretreatment with low-dose GdCl 3 significantly attenuates I/R-induced myocardial apoptosis in rats by suppressing activation of both death receptor and mitochondria-mediated pathways.

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“…Previous research has shown that pharmacological preconditioning of the heart with the K ATP channel opener diazoxide is lost in Kir6.2 Ϫ/Ϫ hearts (52), suggesting that diazoxide is acting primarily through induction of cardioprotective mechanisms associated with plasma membrane K ATP channel activity. Interestingly, it has been shown that AMPK activation plays a key role in mediating the effects of classical ischemic preconditioning (32,47) and stretch-induced preconditioning (24). Therefore, we tested whether the observed diazoxideinduced activation of AMPK is lost in Kir6.2 Ϫ/Ϫ hearts.…”

Section: Pharmacological Activation Of Ampk Is Impaired In Kir62 ϫ/ϫmentioning

confidence: 96%

Hearts lacking plasma membrane K_ATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity

Youssef

Campbell

Barr

et al. 2017

American Journal of Physiology-Heart and Circulatory Physiology

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Cardiac ATP-sensitive K (K) channels couple changes in cellular metabolism to membrane excitability and are activated during metabolic stress, although under basal aerobic conditions, K channels are thought to be predominately closed. Despite intense research into the roles of K channels during metabolic stress, their contribution to aerobic basal cardiac metabolism has not been previously investigated. Hearts from Kir6.2 and Kir6.2 mice were perfused in working mode, and rates of glycolysis, fatty acid oxidation, and glucose oxidation were measured. Changes in activation/expression of proteins regulating metabolism were probed by Western blot analysis. Despite cardiac mechanical function and metabolic efficiency being similar in both groups, hearts from Kir6.2 mice displayed an approximately twofold increase in fatty acid oxidation and a 0.45-fold reduction in glycolytic rates but similar glucose oxidation rates compared with hearts from Kir6.2 mice. Kir6.2 hearts also possessed elevated levels of activated AMP-activated protein kinase (AMPK), higher glycogen content, and reduced mitochondrial density. Moreover, activation of AMPK by isoproterenol or diazoxide was significantly blunted in Kir6.2 hearts. These data indicate that K channel ablation alters aerobic basal cardiac metabolism. The observed increase in fatty acid oxidation and decreased glycolysis before any metabolic insult may contribute to the poor recovery observed in Kir6.2 hearts in response to exercise or ischemia-reperfusion injury. Therefore, K channels may play an important role in the regulation of cardiac metabolism through AMPK signaling. In this study, we show that genetic ablation of plasma membrane ATP-sensitive K channels results in pronounced changes in cardiac metabolic substrate preference and AMP-activated protein kinase activity. These results suggest that ATP-sensitive K channels may play a novel role in regulating metabolism in addition to their well-documented effects on ionic homeostasis during periods of stress.

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Mechanical Stretch-Induced Protection against Myocardial Ischemia-Reperfusion Injury Involves AMP-Activated Protein Kinase

Cited by 15 publications

References 36 publications

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats

Hearts lacking plasma membrane K_ATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity

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Mechanical Stretch-Induced Protection against Myocardial Ischemia-Reperfusion Injury Involves AMP-Activated Protein Kinase

Cited by 15 publications

References 36 publications

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Dystrophin–glycoprotein complex regulates muscle nitric oxide production through mechanoregulation of AMPK signaling

Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats

Hearts lacking plasma membrane KATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity

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Hearts lacking plasma membrane K_ATP channels display changes in basal aerobic metabolic substrate preference and AMPK activity