Reduced Fatty Acid Use from CD36 Deficiency Deteriorates Streptozotocin-Induced Diabetic Cardiomyopathy in Mice

Figures

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  Figure 1. Cardiac contractile dysfunction was more greatly deteriorated in CD36KO-STZ mice. (A) Heart rate (HR) and systolic blood pressure (BP) were not significantly different between the two groups. Heart weight/tibial length (HW/TL) ratio was significantly reduced 16 weeks after STZ treatment. (B) Cardiac function was estimated by echocardiography before STZ treatment and 4, 8, 12 and 16 weeks after (n = 10–12). FS, fractional shortening; LVEDD, left ventricular end-diastolic diameter; LVESD, left ventricular end-systolic diameter. (C) Cardiac fibrosis was estimated by Masson’s trichrome stain (n = 6). Scale bar = 200 µm. * p < 0.05, *** p < 0.001; main effect for genotype. ### p < 0.001; main effect for STZ treatment.

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  Figure 2. Circulating levels of metabolites and uptake of glucose and FA tracers by hearts in absence or presence of STZ treatment. (A) Blood samples were collected after a 6 h fast to measure serum levels of glucose, NEFA, TG, BHB, insulin and lactate (n = 5–7). Glycogen in hearts was also measured. NEFA, non-esterified fatty acids; TG, triacylglycerol; BHB, β-hydroxybutyrate. (B) Uptake of 18F-FDG (glucose tracer) and 125I-BMIPP (FA tracer) by hearts was assessed 2 h after intravenous injection (n = 5–7). * p < 0.05, ** p < 0.01, *** p < 0.001; main effect for genotype. # p < 0.05, ## p < 0.01, ### p < 0.001; main effect for STZ treatment. † p < 0.05, †† p < 0.01, ††† p < 0.001; interaction between genotype and STZ treatment.

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  Figure 3. Glycolytic flux was markedly suppressed by STZ treatment. Hearts were isolated after a 6 h fast for metabolome analysis. (A) Metabolic profiling in glycolysis pathway. G1P-pyruvate, total metabolites from G1P to pyruvate in glycolysis (n = 5–7). (B) Tracer study with 13C6-glucose. After a 6 h fast, hearts were isolated 10 min after intraperitoneal injection of 13C6-glucose (n = 5–7). G1P, glucose 1-phosphate; G6P, glucose 6-phosphate; α-KG, α-ketoglutarate; OAA, oxaloacetate. *** p < 0.001; main effect for genotype. # p < 0.05, ### p < 0.001; main effect for STZ treatment. † p < 0.05, †† p < 0.01; interaction between genotype and STZ treatment.

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  Figure 4. Pool size in TCA cycle was significantly reduced in CD36KO-STZ hearts. Hearts were isolated after a 6 h fast for metabolome analysis. (A) Metabolic profiling in TCA cycle (n = 5–7). TCA cycle, tricarboxylic acid cycle. (B) Tracer study with 13C6-glucose. After a 6 h fast, hearts were isolated 10 min after intraperitoneal injection of 13C6-glucose (n = 5–7). ** p < 0.01, *** p < 0.001; main effect for genotype. ## p < 0.01, ### p < 0.001; main effect for STZ treatment. † p < 0.05, †† p < 0.01, ††† p < 0.001; interaction between genotype and STZ treatment.

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  Figure 5. Accumulation of cardiotoxic lipids was not enhanced in CD36KO-STZ hearts compared to WT-STZ ones. Hearts were isolated after a 6 h fast. Ceramides with different lengths of FAs—C16, C18, C20, C22, C24 and C24:1—were measured (n = 5–7). ** p < 0.01, *** p < 0.001; main effect for genotype. # p < 0.05, ### p < 0.001; main effect for STZ treatment. † p < 0.05, †† p < 0.01; interaction between genotype and STZ treatment.

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  Figure 6. Cardiac contractile dysfunction was synergistically enhanced by STZ and TAC in CD36KO mice. Four weeks after STZ i.p., mice were subjected to TAC. (A) Cardiac contractile function was estimated by echocardiography seven days after TAC (n = 5–9). (B) Uptake of 18F-FDG and 125I-BMIPP was estimated seven days after TAC (n = 6–7). *** p < 0.001; main effect for genotype. ### p < 0.001; main effect for STZ treatment.