High-density lipoprotein determines adult mouse cardiomyocyte fate after hypoxia-reoxygenation through lipoprotein-associated sphingosine 1-phosphate

Abstract

The lipid mediator sphingosine 1-phosphate (S1P) confers survival benefits in cardiomyocytes and isolated hearts subjected to oxidative stress. High-density lipoprotein (HDL) is a major carrier of S1P in the serum, but whether HDL-associated S1P directly mediates survival in a preparation composed exclusively of cardiomyocytes has not been demonstrated. Accordingly, we tested the hypothesis that signal activation and survival during simulated ischemia-reperfusion injury in response to HDL require lipoprotein-associated S1P. As a model, we used adult mouse cardiomyocytes subjected to hypoxia-reoxygenation. Cells were treated or not with autologous mouse HDL, which significantly increased myocyte viability as measured by trypan blue exclusion. This survival effect was abrogated by the S1P(1) and SIP(3) receptor antagonist VPC 23019. The selective S1P(3) antagonist CAY10444, the G(i) antagonist pertussis toxin, the MEK (MAPK/ERK) kinase inhibitor PD-98059, and the phosphoinositide-3 kinase inhibitor wortmannin also inhibited the prosurvival effect of HDL. We observed that HDL activated both Akt (protein kinase B) and the MEK1/2-ERK1/2 pathway and also stimulated phosphorylation of glycogen synthase kinase-3beta. ERK1/2 activation was through an S1P(1) subtype receptor-G(i) protein-dependent pathway, whereas the activation of Akt was inhibited by CAY10444, indicating mediation by S1P(3) subtype receptors. We conclude that HDL, via its cargo of S1P, can directly protect cardiomyocytes against simulated oxidative injury in the absence of vascular effects and that prosurvival signal activation is dependent on both S1P(1) and S1P(3) subtype receptors.

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair

“…Similarly, cardiomyocytes treated with HDL after hypoxia (at reperfusion) show improved cell survival compared to non-treated cells. In this context, the effects of HDL were attributed to PI3K/Akt and ERK1/2 (Tao et al 2010). The possible role of STAT3 has not been investigated in this reperfusion protocol.…”

“…Data from experiments using pharmacological antagonists specific for S1P1, S1P2, and S1P3 receptors demonstrate an inhibition of the HDL actions. For example, several experiments suggest that S1P3 is involved in PI3K/ Akt signalling and that S1P2 and/or S1P1 might be involved in ERK1/2 and STAT3 signalling (Frias et al 2009;Tao et al 2010). S1P2 was shown to play a key role in the HDL-induced protection against the apoptotic effects of doxorubicin (Frias et al 2010).…”

“…In the protection against hypoxia reperfusion injury, a predominant, mediatory role was indicated for the S1P1 and S1P3 receptors, via ERK1/2 and PI3K/Akt activation. No role was attributed to S1P2, but neither was it investigated (Tao et al 2010). The evidence that reinforces the cytoprotective role of S1P comes from experiments, where addition of S1P to reconstituted HDL (rHDL) containing apo A-I improved the protection against the apoptotic action of doxorubicin (Frias et al 2010).…”

Dysfunctional high-density lipoproteins in coronary heart disease: implications for diagnostics and therapy

“…For example, HDL-associated S1P appears to be important for the vasoprotective effects on endothelial cell survival, 104 109 and nitric oxide-dependent vasorelaxation. 20 It also inhibits vascular smooth muscle cell migration and chemokine production, 31, 110 cardiomyocyte apoptosis during hypoxia-reoxygenation, 111,112 and myocardial damage after ischemia/reperfusion. 112,113 Of note, at least some functions of S1P appear to be only exerted if S1P is present on HDL.…”

Information Thermodynamics Derives the Entropy Current of Cell Signal Transduction as a Model of a Binary Coding System

“…Informational thermodynamics for analyzing dynamic biochemical networks and systems biology have also been developed to assess the cell response to external stimuli [1][2][3][4][5][6]. In addition, in in vivo analysis, a significant amount of data on signal transduction has accumulated, and the quantitative analysis of a network of signaling cascades can be performed using new technology [7][8][9][10][11][12][13][14][15][16]. In this study, a quantitative evaluation theory of a signaling cascade is described from the source coding theory of a binary code system applied for biological signal transduction.…”