Sphingosine-1-phosphate reduces ischaemia–reperfusion injury by phosphorylating the gap junction protein Connexin43

Morel, Sandrine; Christoffersen, Christina; Axelsen, Lene Nygaard; Montecucco, Fabrizio; Rochemont, Viviane; Frias, Miguel; Mach, François; James, Richard; Naus, Christian C.; Chanson, Marc; Lampe, Paul D.; Nielsen, Morten Schak; Nielsen, Lars Bo; Kwak, Brenda R.

doi:10.1093/cvr/cvw004

Cited by 59 publications

(49 citation statements)

References 44 publications

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“…Another study also demonstrated that S1P 2 and S1P 3 antagonists block S1P mediated cardioprotection [65]. The studies reported here show that signaling via the S1P 3 receptor to RhoA in cardiomyocytes of the isolated, perfused heart is both sufficient and required for cardioprotection in ex vivo I/R.…”

Section: Discussionsupporting

confidence: 66%

Selective coupling of the S1P 3 receptor subtype to S1P-mediated RhoA activation and cardioprotection

Yung

Brand

Xiang

et al. 2017

Journal of Molecular and Cellular Cardiology

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Sphingosine-1-phosphate (S1P), a bioactive lysophospholipid, is generated and released at sites of tissue injury in the heart and can act on S1P1, S1P2, and S1P3 receptor subtypes to affect cardiovascular responses. We established that S1P causes little phosphoinositide hydrolysis and does not induce hypertrophy indicating that it does not cause receptor coupling to Gq. We previously demonstrated that S1P confers cardioprotection against ischemia/reperfusion by activating RhoA and its downstream effector PKD. The S1P receptor subtypes and G proteins that regulate RhoA activation and downstream responses in the heart have not been determined. Using siRNA or pertussis toxin to inhibit different G proteins in NRVMs we established that S1P regulates RhoA activation through Gα13 but not Gα12, Gαq, or Gαi. Knockdown of the three major S1P receptors using siRNA demonstrated a requirement for S1P3 in RhoA activation and subsequent phosphorylation of PKD, and this was confirmed in studies using isolated hearts from S1P3 knockout (KO) mice. S1P treatment reduced infarct size induced by ischemia/reperfusion in Langendorff perfused wild-type (WT) hearts and this protection was abolished in the S1P3 KO mouse heart. CYM-51736, an S1P3-specific agonist, also decreased infarct size after ischemia/reperfusion to a degree similar to that achieved by S1P. The finding that S1P3 receptor- and Gα13-mediated RhoA activation is responsible for protection against ischemia/reperfusion suggests that selective targeting of S1P3 receptors could provide therapeutic benefits in ischemic heart disease.

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Section: Discussionsupporting

confidence: 66%

Selective coupling of the S1P 3 receptor subtype to S1P-mediated RhoA activation and cardioprotection

Yung

Brand

Xiang

et al. 2017

Journal of Molecular and Cellular Cardiology

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“…HDL infusion or S1P 1 agonists have been previously shown to protect the myocardium from MI/R injury (38–41). The effect of ApoM-Fc–S1P was associated with reduced infiltration of neutrophils into the myocardium.…”

Section: Discussionmentioning

confidence: 99%

An engineered S1P chaperone attenuates hypertension and ischemic injury

et al. 2017

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Endothelial dysfunction, a hallmark of vascular disease, is restored by plasma high-density lipoprotein (HDL). However, a generalized increase in HDL abundance is not beneficial, suggesting that specific HDL species mediate protective effects. Apolipoprotein M–containing HDL (ApoM+HDL), which carries the bioactive lipid sphingosine 1-phosphate (S1P), promotes endothelial function by activating G protein–coupled S1P receptors. Moreover, HDL-bound S1P is limiting in several inflammatory, metabolic, and vascular diseases. We report the development of a soluble carrier for S1P, ApoM-Fc, which activated S1P receptors in a sustained manner and promoted endothelial function. In contrast, ApoM-Fc did not modulate circulating lymphocyte numbers, suggesting that it specifically activated endothelial S1P receptors. ApoM-Fc administration reduced blood pressure in hypertensive mice, attenuated myocardial damage after ischemia/reperfusion injury, and reduced brain infarct volume in the middle cerebral artery occlusion model of stroke. Our proof-of-concept study suggests that selective and sustained targeting of endothelial S1P receptors by ApoM-Fc could be a viable therapeutic strategy in vascular diseases.

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“…Accordingly, HDL from apoM-TG mice stimulates S1P–dependent signaling mechanisms in endothelial cells while HDL from apoM null mice does not (87). The relationship between apoM expression and S1P-mediated cardioprotection has been recently evaluated in wildtype and transgenic mice undergoing coronary artery ligation and reperfusion (88,89). Plasma S1P levels were increased in apoM-TG mice by approximately 250% compared to wildtype mice.…”

Section: Sphingosine 1-phosphate and Cardioprotectionmentioning

confidence: 99%

“…In vitro analyses of neonatal rat ventricular cardiomyocytes showed that S1P induced phosphorylation of Connexin43 (Cx43) and reduced gap junctional communication between cardiomyocytes (88). It was proposed that S1P protects the heart against I/R injury by inhibiting cell-cell coupling (88,89). In this manner, the passage of death signals through gap junctions is reduced, resulting in attenuation of I/R-induced cardiomyocyte injury (89).…”

Section: Sphingosine 1-phosphate and Cardioprotectionmentioning

confidence: 99%

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High-density lipoprotein, mitochondrial dysfunction and cell survival mechanisms

White

Giordano

Anantharamaiah

2016

Chemistry and Physics of Lipids

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Ischemic injury is associated with acute myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting and open heart surgery. The timely re-establishment of blood flow is critical in order to minimize cardiac complications. Reperfusion after a prolonged ischemic period, however, can induce severe cardiomyocyte dysfunction with mitochondria serving as a major target of ischemia/reperfusion (I/R) injury. An increase in the formation of reactive oxygen species (ROS) induces damage to mitochondrial respiratory complexes leading to uncoupling of oxidative phosphorylation. Mitochondrial membrane perturbations also contribute to calcium overload, opening of the mitochondrial permeability transition pore (mPTP) and the release of apoptotic mediators into the cytoplasm. Clinical and experimental studies show that ischemic preconditioning (ICPRE) and postconditioning (ICPOST) attenuate mitochondrial injury and improve cardiac function in the context of I/R injury. This is achieved by the activation of two principal cell survival cascades: 1) the Reperfusion Injury Salvage Kinase (RISK) pathway; and 2) the Survivor Activating Factor Enhancement (SAFE) pathway. Recent data suggest that high density lipoprotein (HDL) mimics the effects of conditioning protocols and attenuates myocardial I/R injury via activation of the RISK and SAFE signaling cascades. In this review, we discuss the roles of apolipoproteinA-I (apoA-I), the major protein constituent of HDL, and sphingosine 1-phosphate (S1P), a lysosphingolipid associated with small, dense HDL particles as mediators of cardiomyocyte survival. Both apoA-I and S1P exert an infarct-sparing effect by preventing ROS-dependent injury and inhibiting the opening of the mPTP.

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Sphingosine-1-phosphate reduces ischaemia–reperfusion injury by phosphorylating the gap junction protein Connexin43

Abstract: Our study reveals an important molecular pathway by which modulating the apoM/S1P axis has a therapeutic potential in the fight against I/R injury in the heart.

Cited by 59 publications

References 44 publications

Selective coupling of the S1P 3 receptor subtype to S1P-mediated RhoA activation and cardioprotection

Selective coupling of the S1P 3 receptor subtype to S1P-mediated RhoA activation and cardioprotection

An engineered S1P chaperone attenuates hypertension and ischemic injury

High-density lipoprotein, mitochondrial dysfunction and cell survival mechanisms

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