4.2 CD36 and diabetic cardiomyopathy
The typical characteristic of diabetic cardiomyopathy is the altered lipid metabolism and impaired insulin signaling pathways(Jia et al., 2016; Carpentier, 2018; Joubert et al., 2019). In the basic conditions, CD36 on the cardiac sarcolemma is significantly increased in obese Zuker rats(Coort et al., 2004), db/db mice(Carley and Severson, 2008) and high-fat-fed rats(Ouwens et al., 2007). The upregulation of CD36 has also been confirmed in cardiomyocytes of patients with diabetic cardiomyopathy(Garcia-Rua et al., 2012).
The increase of CD36 on the sarcolemma in diabetic cardiomyopathy may be attributed to hyperinsulinemia, hyperglycemia, and hyperlipidemia. In the early stages of diabetes, insulin is at high levels(Paolillo et al., 2019), Luiken JJ et al. found that insulin stimulation in isolated rat myocardial cells resulted in a 1.5-fold increase in CD36 on the sarcolemma and a 62% decrease in intracellular CD36, which suggested that insulin could effectively promote the translocation of CD36(Luiken et al., 2002) (Figure 3). Besides, chronic insulin stimulation also induces CD36 mRNA translation by activating the transcription factor forkhead box O1 (FOXO1), which further facilitates CD36 protein synthesis(Chistiakov et al., 2017) (Figure 3). In the late stage of diabetes, although the insulin level has decreased significantly, and the cardiomyocytes are not sensitive to insulin at this time due to insulin resistance, but CD36 has been already permanently transferred to the myometrium during the early stage(Ouwens et al., 2007). As a result, the decline of insulin doesn’t change the facts that fatty acids have been taken into the cardiomyocytes in quantity. Similar to chronic insulin stimulation, high glucose stimulation could increase CD36 mRNA translation(Griffin et al., 2001), followed by increased CD36 expression, and palmitic acid stimulation could induce membrane translocation of CD36(Angin et al., 2012). In the advanced stage of diabetes, hyperglycemia and hypertriglyceridemia may occur, thus further promote CD36 expression and increase its membrane distribution(Alonso et al., 2018). In addition to external factors such as insulin, glucose and lipids, the latest researches suggest that the increase in CD36 in diabetic cardiomyopathy is also associated with the regulation of microRNA. MiR-320 which acts as a small activating RNA in the nucleus is highly expressed in diabetic cardiomyopathy mice, and promotes CD36’s expression by directly acting on its nuclear transcription(Li et al., 2019) (Figure 3). In contrast, miR-200b-3p is remarkably reduced in diabetes cardiomyopathy, which is an effective inhibitor of CD36 (Figure 3).
CD36 increases in diabetic cardiomyopathy, which in turn worsens heart function(Luiken, 2009). The increased distribution of CD36 on the myometrium result in the intake of a large amount of fatty acids. Fatty acids in the cytoplasm could activate peroxisome proliferator-activated receptors (PPAR)(Glatz and Luiken, 2017), thereby inducing the up-regulation of enzymes necessary for mitochondrial β-oxidation, leading to a significant increase in fatty acid oxidation rates. However, the rate of fatty acid uptake and storage is higher than the rate of oxidation, thus resulting in the accumulation of lipids in the cell (Figure 3). Excessive lipid intermediates, including diacylglycerol and ceramide, have been shown to induce insulin resistance(Petersen and Shulman, 2017), triggers myocardial contractile dysfunction(Chistiakov et al., 2017). At the same time, high levels of β-oxidation of fatty acids produce a large amount of reactive oxygen species (ROS)(Cortassa et al., 2017), which can also induce inflammation(Agita and Alsagaff, 2017) and insulin resistance(Di Meo et al., 2017; Sung et al., 2019) to aggravate myocardial contractile dysfunction (Figure 3). Besides. lipids could directly lead to contractile dysfunction by promoting myocardial cell apoptosis(Zhou et al., 2018). Therefore, inhibiting the uptake of long-chain fatty acids by targeting CD36 is the preferred strategy to reduce cardiac insulin resistance and ultimately prevent diabetic heart failure.
Several studies have proved that reducing the distribution of CD36 on the sarcolemma and thereby inhibiting the uptake of LCFA do help to improve the heart function of diabetic cardiomyopathy(Angin et al., 2012). For example, myosin heavy chain (MHC) -PPARα overexpressed mice shows severe cardiomyocyte lipid accumulation and cardiac dysfunction(Yang et al., 2007). However, due to the lack of CD36, the offspring produced by crossing MHC-PPARα mice with CD36-deficient mice (MHC-PPARα/CD36-/-mice) improves triglycerides accumulation and cardiac dysfunction under basic conditions and in a high-fat diet. Glucagon-like peptide-1 could eliminate the lipo-toxicity of diabetic cardiomyopathy by stimulating protein kinase A (PKA) inhibition of PPARα -CD36 pathway(Wu et al., 2018). Exogenous H2S protects diabetic hearts by inhibiting the translocation of CD36(Yu et al., 2020). N-Acetylcysteine also restored Sevo-postC cardioprotection in diabetes by reducing Foxo1 and CD36(Lin et al., 2016). Fibroblast growth factor 21(FGF21) deletion aggravates cardiac lipid accumulation by up-regulating cardiac Nrf2-driven CD36 expression(Yan et al., 2015). Thus FGF21 is a potential agent to reduce lipid accumulation and ameliorates diabetic cardiomyopathy by down-regulating the expression of CD36.
4.3 CD36 and cardiac hypertrophy
4.3.1 CD36 in hereditary hypertrophic cardiomyopathy
Hereditary hypertrophic cardiomyopathy (HCM) is a disease with cardiac hypertrophy as the main pathological manifestation, and it is caused by a dominant mutation in the gene encoding cardiac sarcomeric protein(Sequeira et al., 2019). A survey about the CD36 and hereditary hypertrophic cardiomyopathy patients shows that 37.9% of HCM patients with asymmetric ventricular septal hypertrophy had a loss of CD36 protein(Tanaka et al., 1997), which is accompanied by defective myocardial long-chain fatty acid intake, suggesting that the reduced CD36 may play a role in the pathogenesis of hereditary hypertrophy. The relationship of CD36 translocation and left ventricular contractile dysfunction is verified in HCM mice(Tanaka et al., 1997; Magida and Leinwand, 2014). Owing to the decrease of CD36 translocation to the plasm membrane, ATP and triglyceride in the myocardium dramatically decrease. Although the mechanism of how CD36 decreases in hereditary hypertrophic cardiomyopathy remains to be investigated, increasing CD36 and improving fatty acid intake may provide a new solution for the treatment of hereditary hypertrophic cardiomyopathy.
4.3.2 CD36 in pathological/ physiological cardiac hypertrophy
Differing from hereditary hypertrophic cardiomyopathy generated by genetic mutations, secondary cardiac hypertrophy is mostly caused by external stress including pressure overload or physical exercise. And it is naturally divided into physiological cardiac hypertrophy and pathological cardiac hypertrophy according to different stimulus factors and outcomes. Changes in CD36 in two different types of hypertrophy hearts were first demonstrated in 2013(Dobrzyn et al., 2013). Exercise training significantly increases the expression of CD36 in the heart, but pressure overload reduces the expression of CD36(Iemitsu et al., 2003). The decrease in CD36 in pathological cardiac hypertrophy and the upregulation in physiological cardiac hypertrophy may be related to PPARα and peroxisome proliferator-activated receptor γ coactivator-1α (PGC1α). Physical exercise increases the expression of PPARα(Santos et al., 2016; Broderick et al., 2018) and PGC1α (Tao et al., 2015; Deloux et al., 2017)in the heart, while cardiac pressure overload reduces both of them(Oka et al., 2015; Karam et al., 2017) (Figure 4). The promoter region of CD36 contains PPARα response elements(van der Meer et al., 2010). And it has been shown that nuclear receptor PPARα and nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ) regulate CD36 expression in macrophages and cardiac microvascular endothelial cells(Madonna et al., 2011; He et al., 2019).
As mentioned before, when myocardial cells are facing a crisis of ischemia and hypoxia, metabolism is remodeled. As for hypoxic pathological cardiac hypertrophy(Tham et al., 2015), early and timely reduction of the distribution of CD36 on the cell membrane helps to eliminate the injury brought by subsequent large intake of fatty acids. The reduction of CD36 not only promotes the substrate transition of fatty acids to glucose(Umbarawan et al., 2018b), but also eliminates the accumulation of toxic lipid intermediates. However, the reduction of CD36 may ultimately shorten the energy supply in the chronic stage of pathological cardiac hypertrophy. Glucose uptake and glucose oxidation increase in the early stage to sustain the energy generation, but it eventually decreased in the late stage(Iemitsu et al., 2003). And, glycolysis and energy generated from other substrates (lactic acid, branched-chain amino acids and ketone bodies) couldn’t compensate for the reduction of fatty acid oxidation and glucose oxidation, putting the heart in an insufficient cardiac energy state (Figure 4). Besides, Although the reduction of CD36 leads to a remarkable decline in the overall intake of fatty acids, studies have proved that fat synthesis-related enzymes , including sterol-responsive element-binding protein-1c (SREBP -1c), stearoyl-CoA desaturase 1 (SCD1), stearoyl-CoA desaturase 2 (SCD2) and Glycerol-3-phosphate acyltransferase (GPAT) et al., are not down-regulated in pathological cardiac hypertrophic cardiomyocytes (Figure 4). But, the activity and content of hormone-sensitive lipase (HSL) and diacylglycerol lipase (DAGL) that break down fat decrease, resulting in a 31% increase in triglycerides and a 200% increase in diacylglycerol in myocardial cells(Tanaka et al., 1997) (Figure 4). insulin resistance caused by accumulated toxic lipids further exacerbates the lack of energy supply in the heart. Therefore, CD36 down-regulation is beneficial for the adaptive pathological cardiac hypertrophy, while is detrimental for maladaptive pathological cardiac hypertrophy.
Recent studies on CD36 cardiac-specific knockout mice and systemic knockout mice have demonstrated the role of CD36 in pathological cardiac hypertrophy. CD36 cardiac-specific knockout mice rapidly transferred from compensatory cardiac hypertrophy to heart failure due to the imbalance of energy. Comparatively, CD36 systemic knockout mice show pronounced myocardial interstitial fibrosis, cardiac enlargement and contractile dysfunction than wild-type mice after transverse aortic constriction (TAC) surgery(Nakatani et al., 2019). The myocardium of CD36KO-TAC leads to insufficient energy supply, not only due to the decrease of CD36, but also because of the increase of de novo amino acid synthesis from glucose, which further reduces the size of the high-energy phosphate pool(Umbarawan et al., 2018a). But, whether overexpression of CD36 relieves the energy deficiency in the pathological cardiac hypertrophy and in turn saves the failing heart caused by cardiac pressure overload needs further investigation. And it is certain that increasing the supply of fatty acids in myocardial cells to expand high-energy phosphate pool is beneficial for hypertrophic myocardium. Because even in the case of a decrease in medium-chain acetyl-CoA dehydrogenase, providing medium-chain fatty acids for cardiomyocytes lacking CD36 and bypassing long-chain fatty acids can still relieve cardiac pressure overload-induced heart failure(Sung et al., 2017).