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).