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).