Role of PI3Kα and sarcolemmal ATP-sensitive potassium channels in epoxyeicosatrienoic acid mediated cardioprotection

Batchu, Sri Nagarjun; Chaudhary, Ketul R; El‐Sikhry, Haitham; Yang, Wei; Light, Peter E.; Oudit, Gavin Y.; Seubert, John M.

doi:10.1016/j.yjmcc.2012.04.008

Cited by 39 publications

(29 citation statements)

References 38 publications

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“…At 100 nM, addition of PI-103 did not affect basal contractility or recovery after IR (not shown), consistent with previous reports [27]. Comparable to LY, co-administration of PI-103 did not affect ouabain-induced increased in LVDP (6A, t= 33 to 37 min), but significantly blunted OPC-induced post-ischemic recovery.…”

Section: Resultssupporting

confidence: 90%

“…Both canonical PI3K IA- (insulin, insulin-like growth factor, epidermal growth factor) and IB- (acetylcholine, opioid, bradykinin) activators can trigger preconditioning, but the respective roles of PI3K IA and IB in different forms of preconditioning have not been specifically evaluated in most instances [6, 18, 20-24]. Exceptions include IPC, in which PI3K IB requirement has been established [25, 26], as well as adenosine (PI3K-IB) [25], and epoxyeicosatrienoic acid (PI3K-IA) [27]. At least theoretically, distinct PI3K Class I requirements could influence the efficiency of preconditioning treatments in subsets of patients at risk for myocardial infarction and presenting with medication and comorbidities that differentially affect Class IA and IB PI3K [28-30].…”

Section: Introductionmentioning

confidence: 99%

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Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning

Duan

Madan

et al. 2015

Journal of Molecular and Cellular Cardiology

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Acute myocardial infarction, the clinical manifestation of ischemia-reperfusion (IR) injury, is a leading cause of death worldwide. Like ischemic preconditioning (IPC) induced by brief episodes of ischemia and reperfusion, ouabain preconditioning (OPC) mediated by Na/K-ATPase signaling protects the heart against IR injury. Class I PI3K activation is required for IPC, but its role in OPC has not been investigated. While PI3K-IB is critical to IPC, studies have suggested that ouabain signaling is PI3K-IA-specific. Hence, a pharmacological approach was used to test the hypothesis that OPC and IPC rely on distinct PI3K-I isoforms. In Langendorff-perfused mouse hearts, OPC was initiated by 4 min of ouabain 10 μM and IPC was triggered by 4 cycles of 5 min ischemia and reperfusion prior to 40 min of global ischemia and 30 min of reperfusion. Without affecting PI3K-IB, ouabain doubled PI3K-IA activity and Akt phosphorylation at Ser473. IPC and OPC significantly preserved cardiac contractile function and tissue viability as evidenced by left ventricular developed pressure and end-diastolic pressure recovery, reduced lactate dehydrogenase release, and decreased infarct size. OPC protection was blunted by the PI3K-IA inhibitor PI-103, but not by the PI3K-IB inhibitor AS-604850. In contrast, IPC-mediated protection was not affected by PI-103 but was blocked by AS-604850, suggesting that PI3K-IA activation is required for OPC while PI3K-IB activation is needed for IPC. Mechanistically, PI3K-IA activity is required for ouabain-induced Akt activation but not PKCε translocation. However, in contrast to PKCε translocation which is critical to protection, Akt activity was not required for OPC. Further studies shall reveal the identity of the downstream targets of this new PI3K IA-dependent branch of OPC. These findings may be of clinical relevance in patients at risk for myocardial infarction with underlying diseases and/or medication that could differentially affect the integrity of cardiac PI3K-IA and IB pathways.

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Section: Resultssupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning

Duan

Madan

et al. 2015

Journal of Molecular and Cellular Cardiology

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“…The involvement of PI3K signaling in EET-mediated activation of PPARγ is possible mechanism of action. Our previously published studies suggest that EET triggered biologically effects might involve PI3K (Batchu et al, 2011, 2012). Evidence from the literature also suggests a complex interplay between PI3K and PPARγ pathways (Chuang et al, 2007; Mishra et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

PPARÎ³ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS

et al. 2014

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Lipopolysaccharide (LPS) is a bacterial wall endotoxin producing many pathophysiological conditions including myocardial inflammation leading to cardiotoxicity. Epoxyeicosatrienoic acids (EETs) are biologically active metabolites of arachidonic acids capable of activating protective cellular pathways in response to stress stimuli. EETs evoke a plethora of pathways limiting impairments of cellular structures, reducing cell death, and promoting anti-inflammatory reactions in various cell types. Considering EETs are capable of producing various biological protective effects, we hypothesized that EETs would protect rat neonatal cardiomyocytes (NCM) against LPS-induced cytotoxicity. In this study, we used a dual-acting, synthetic analog of EETs, UA-8 [13-(3-propylureido)tridec-8-enoic acid], possessing both EET-mimetic and soluble epoxide hydrolase selective inhibitory properties and 14,15-EET as a model of canonical EET molecules. We found that both UA-8 and 14,15-EET significantly improved cell viability and mitochondrial function of cardiomyocytes exposed to LPS. Furthermore, treatment with UA-8 or 14,15-EET resulted in significant attenuation of LPS-triggered pro-inflammatory response, caspase-3 activation and reduction in the total antioxidant capacity in cardiomyocytes. Importantly, EET-mediated effects were significantly reduced by pharmacological inhibition of peroxisome proliferator-activated receptors γ (PPARγ) suggesting that PPARγ signaling was required for EETs exerted protective effects. Data presented in the current study demonstrate that activation of PPARγ signaling plays a crucial role in EET-mediated protection against LPS-cytotoxicity in cardiomyocytes.

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Section: B Atp-sensitive Potassium Channelsmentioning

confidence: 99%

“…In this case, it seems that the 11,12-EET-induced activation of K ATP channels is dependent on the G s protein and the activation of PKA (Ye et al, 2005) and/or the phosphatidylinositol 3-kinase (PI3-K) (Batchu et al, 2012a), albeit with eventual organ-specific differences in the mechanism of channel activation Bodiga et al, 2009). On the whole, EET-induced activation of K ATP channels seems to be cardioprotective and EETs can regulate cardiac electrophysiology and prevent the increase in intracellular Ca 2+ that is generally associated with ischemia-reperfusion injury (Batchu et al, 2012a). More recently, the cardioprotective effect of EETs administered prior to ischemia was attributed to the activation of the eNOS and increased NO production, whereas K ATP channel activation and the mitochondrial permeability transition pore were involved in the beneficial effects of the EETs when administered just prior to reperfusion (Gross et al, 2013).…”

Section: B Atp-sensitive Potassium Channelsmentioning

confidence: 99%

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

2014

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Role of PI3Kα and sarcolemmal ATP-sensitive potassium channels in epoxyeicosatrienoic acid mediated cardioprotection

Cited by 39 publications

References 38 publications

Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning

Role of phosphoinositide 3-kinase IA (PI3K-IA) activation in cardioprotection induced by ouabain preconditioning

PPARÎ³ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS

The Pharmacology of the Cytochrome P450 Epoxygenase/Soluble Epoxide Hydrolase Axis in the Vasculature and Cardiovascular Disease

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