4.1 CD36 and ischemia/reperfusion
Ischemia/reperfusion is characterized by the abruptly interruption of blood flow and subsequent restoration of blood flow(Lejay et al., 2016). The cutoff of oxygen and nutrition results in various metabolic changes(Lesnefsky et al., 2017), including lipid metabolism alterations. The change of CD36 in ischemia/reperfusion has been shown by using (3) H-labeled metabolic substrates to measure the metabolic changes of Wistar rat heart at different stages during ischemia/reperfusion(Heather et al., 2013). During ischemia, the CD36 of the sarcolemma is downregulated by 32%, and the fatty acid oxidation rate decreases by 95%. In the reperfusion stage, CD36 level remains low, but the fatty acid oxidation rate returned to the pre-ischemic state(Heather et al., 2013). The increased pH of the endosome may contribute to the low level of CD36 throughout the whole ischemia/reperfusion period(Steinbusch et al., 2010). Translocation of CD36 to the sarcolemma is significantly enhanced when the pH of the endosome is high, while a decrease in pH inhibits this translocation. During ischemia, myocardial glycolysis increases by 86% and lactic acid level increases by 7 folds(Heather et al., 2013) (Figure 2), which lead to a low pH state and subsequently suppresses the CD36 translocation. When shifting to the reperfusion phase, the lactic acid in cardiomyocytes could not be effectively eliminated in a short period of time, the cells may still be at a low pH status and CD36 translocation is still suppressed (Figure 2).
With same oxygen consumption, glucose provides more energy than lipid, so it is preferred to maintenance myocardial function(Fukushima et al., 2015; Umbarawan et al., 2018b). The reduction of CD36 is beneficial to the conversion of metabolic substrates from fatty acids to glucose during hypoxia. Thus the constantly low level of CD36 may help cardiomyocytes to maintain energy balance (Figure 2). What’s more, the rate of fatty acid oxidation in cardiomyocytes in ischemia is reduced to 5% of basal states(Heather et al., 2013). A relatively low CD36 avoids the accumulation of triglycerides in cytosol by reducing the absorption of fatty acids (Figure 2). High concentrations of fatty acids in the cardiomyocytes could reduce the recovery of ischemic heart function during the reperfusion stage by triggering insulin resistance and cardiomyocytes apoptosis(Adrian et al., 2017; Jelenik et al., 2018; Liu et al., 2018b). Therefore, the reduction of CD36 during ischemia benefits to the heart by avoiding excessive accumulation of triglycerides, and CD36 decreasing during ischemia is a favorable adaptation for cardiomyocytes to survive.
Focusing on inhibiting CD36 function, therapeutic strategies for ischemia-reperfusion have been developed. Mansor LS et al corrected post-hypoxia/reoxygenation cardiac metabolic disorders by injecting a CD36 inhibitor sulfo-N-succinimide oleate into the heart of type 2 diabetic male Wistar rats 4 minutes before hypoxia(Mansor et al., 2017). Pre-injection of selective CD36 ligand EP 80317 and azeptide CP-3(iv) in mice significantly reduced myocardial infarct size(Bessi et al., 2012; Huynh et al., 2018). Exenatide, a small molecule drug that generally regulates glucose metabolism, has also been shown to improve cardiac function after cardiac ischemia-reperfusion injury by inhibiting the translocation of CD36(Zheng et al., 2017).
Drug studies provided strong evidence that inhibiting the function of CD36 contributes to the recovery of heart function, but the most direct evidence comes from heart CD36-knockout (cCD36KO) mice. Inducible cardiomyocyte-specific CD36 ablation does not alter cardiac morphology, while improves functional recovery after ischemia/reperfusion(Nagendran et al., 2013). The decrease in fatty acid oxidation rate caused by the decrease of CD36 lays the foundation for increasing the rate of glucose oxidation. And it was proved that this recovery is due to the lower hydrogen ion concentration resulting from the uncoupling of glycolysis from glucose oxidation produced before and after ischemia(Nagendran et al., 2013). However, CD36 systemic knockout mice still suffered from severe ischemia-reperfusion injury(Cera et al., 2010). Presumably, it is the general reduction of CD36 that matters. Not restricted in the heart, systemic metabolic changes occur in a vast of tissues in the systemic knockout mice, and due to various potential adaptive adjustments from the embryonic stage, these mice may be significantly different from heart-specific knockout mice.
However, some studies about spontaneously hypertensive rats on ischemia/reperfusion have challenged the protective effect of CD36 decline. Instead of the inhibition of CD36, the overexpression of CD36 in SHR rats reduced the infarct size, and the underlying mechanism has not been clarified. Giving that the model already has the pathological factor of hypertension, it is possible that the overexpression of CD36 reduce the myocardial injury risk brought by hypertension and indirectly protect the infarcted myocardium caused by ischemia/reperfusion(Neckar et al., 2012).