Post-translational modifications, a key process in CD36 function: lessons from the spontaneously hypertensive rat...

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• CD36 is crucial for cardiac long chain fatty acid (LCFA) metabolism and heart disease development.
• The functional consequences of genetic variations in CD36, particularly in disease models, are not fully understood.

Purpose of the Study:

• To investigate if defective CD36 post-translational modifications (PTMs) cause reduced cardiac LCFA utilization in spontaneously hypertensive rats (SHR) before the onset of cardiac hypertrophy.
• To explore the role of specific CD36 PTMs in regulating its membrane localization and function in LCFA metabolism.

Main Methods:

• Ex vivo heart perfusion using (13)C-labeled substrates in 7-week-old SHR and control rats.
• Biochemical techniques to assess protein levels, distribution, PTMs (N-glycosylation, O-linked-β-N-acetylglucosamine), and malonyl-CoA levels.

Main Results:

• SHR hearts showed significantly reduced LCFA contribution to β-oxidation (-40%) and altered triglyceride levels (+2.8 folds) compared to controls.
• These metabolic changes were not linked to transcriptional alterations or malonyl-CoA levels.
• SHR hearts exhibited decreased membrane-associated CD36 protein levels and altered N-glycosylation, with O-linked-β-N-acetylglucosamine being critical for CD36 membrane recruitment and LCFA utilization.

Conclusions:

• Defective CD36 post-translational modifications, specifically N-glycosylation, impair cardiac LCFA metabolism in SHR prior to hypertrophy.
• O-linked-β-N-acetylglucosamine is essential for CD36's membrane localization and function in cardiac LCFA uptake.
• These findings provide insights into CD36's role in heart disease pathogenesis and suggest potential therapeutic targets.