Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery

Nagendran, Jeevan; Pulinilkunnil, Thomas; Kienesberger, Petra C.; Sung, Miranda M.; Fung, David; Febbraio, Maria; Dyck, Jason R.B.

doi:10.1016/j.yjmcc.2013.07.020

Cited by 67 publications

(54 citation statements)

References 46 publications

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“…External stimuli such as insulin, diet, caffeine, etc., can trigger relocalization of CD36 to the sarcolemma (25,41,42). Similarly, deficiency of CD36 in hearts can influence fatty acid uptake and oxidation, as reported in compromised recovery from ischemic injury (43,44). Our combined data in both RV tissue from transgenic mice and BMPR2 mutant cardiomyocytes demonstrate that BMPR2 mutation can independently up-regulate CD36 at the protein level, not at the mRNA transcription level, and trigger relocalization of CD36 in cultured cardiomyocytes.…”

Section: Discussionsupporting

confidence: 67%

Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle

Talati

Brittain²,

Fessel

et al. 2016

Am J Respir Crit Care Med

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Rationale: In heritable pulmonary arterial hypertension with germline mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, right ventricle (RV) dysfunction is associated with RV lipotoxicity; however, the underlying mechanism for lipid accumulation is not known.Objectives: We hypothesized that lipid accumulation in cardiomyocytes with BMPR2 mutation occurs owing to alterations in lipid transport and impaired fatty acid oxidation (FAO), which is exacerbated by a high-lipid (Western) diet (WD).Methods: We used a transgenic mouse model of pulmonary arterial hypertension with mutant BMPR2 and generated a cardiomyocyte cell line with BMPR2 mutation. Electron microscopy and metabolomic analysis were performed on mouse RVs.Measurements and Main Results: By metabolomics analysis, we found an increase in long-chain fatty acids in BMPR2 mutant mouse RVs compared with controls, which correlated with cardiac index. BMPR2-mutant cardiomyocytes had increased lipid compared with controls. Direct measurement of FAO in the WD-fed BMPR2-mutant RV showed impaired palmitate-linked oxygen consumption, and metabolomics analysis showed reduced indices of FAO. Using both mutant BMPR2 mouse RVs and cardiomyocytes, we found an increase in the uptake of 14 C-palmitate and fatty acid transporter CD36 that was further exacerbated by WD.Conclusions: Taken together, our data suggest that impaired FAO and increased expression of the lipid transporter CD36 are key mechanisms underlying lipid deposition in the BMPR2-mutant RV, which are exacerbated in the presence of dietary lipids. These findings suggest important features leading to RV lipotoxicity in pulmonary arterial hypertension and may point to novel areas of therapeutic intervention.

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Section: Discussionsupporting

confidence: 67%

Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle

Talati

Brittain²,

Fessel

et al. 2016

Am J Respir Crit Care Med

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“…The observations that cardiomyocyte-specific Cd36 deletion alters heart metabolism [56] and that changes in CD36 expression modulate cardiomyocyte FFA uptake [27] are consistent with a role of cardiomyocyte CD36 in handling of FFAs after their transendothelial release.…”

Section: Heart Fa Uptake: Metabolic Flexibility and The Evolving Rmentioning

confidence: 65%

CD36 actions in the heart: Lipids, calcium, inflammation, repair and more?

Abumrad

Goldberg

2016

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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CD36 is a multifunctional immuno-metabolic receptor with many ligands. One of its physiological functions in the heart is the high-affinity uptake of long-chain fatty acids (FAs) from albumin and triglyceride rich lipoproteins. CD36 deletion markedly reduces myocardial FA uptake in rodents and humans. The protein is expressed on endothelial cells and cardiomyocytes and at both sites is likely to contribute to FA uptake by the myocardium. CD36 also transduces intracellular signaling events that influence how the FA is utilized and mediate metabolic effects of FA in the heart. CD36 mediated signaling regulates AMPK activation in a way that adjusts oxidation to FA uptake. It also impacts remodeling of myocardial phospholipids and eicosanoid production, effects exerted via influencing intracellular calcium (iCa2+) and the activation of phospholipases. Under excessive FA supply CD36 contributes to lipid accumulation, inflammation and dysfunction. However, it is also important for myocardial repair after injury via its contribution to immune cell clearance of apoptotic cells. This review describes recent progress regarding the multiple actions of CD36 in the heart and highlights those areas requiring future investigation.

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“…By regulating heart and skeletal muscle FA delivery and glucose utilization, EC CD36 is a major factor affecting tissue fuel selection and systemic metabolism. Whether EC CD36 actions are beneficial for normal or diseased hearts is uncertain (48)(49)(50) and probably depends on the physiologic situation. Reduction of LCFA uptake leads to impaired energy production during fasting or exercise, but also protects against excess lipid accumulation (lipotoxicity) (51) and improve glucose utilization during hypoxia (52).…”

Section: Discussionmentioning

confidence: 99%