CD36 overexpression predisposes to arrhythmias but reduces infarct size in spontaneously hypertensive rats: gene expression profile analysis
Abstrakt
CD36 fatty acid translocase plays a key role in supplying heart with its major energy substrate, long-chain fatty acids (FA). Previously, we found that the spontaneously hypertensive rat (SHR) harbors a deletion variant of Cd36 gene that results in reduced transport of long-chain FA into cardiomyocytes and predisposes the SHR to cardiac hypertrophy.
In the current study, we analyzed the effects of mutant Cd36 on susceptibility to ischemic ventricular arrhythmias and myocardial infarction in adult SHR-Cd36 transgenic rats with wild type Cd36 compared to age-matched SHR controls. Using an open-chest model of coronary artery occlusion, we found that SHR-Cd36 transgenic rats showed profound arrhythmogenesis resulting in significantly increased duration of tachyarrhythmias (207+-48s vs. 55+-21s, P is lower then 0.05), total number of premature ventricular complexes (2623+-517 vs. 849+-250, P is lower then 0.05) and arrhythmia score (3.86+-0.18 vs. 3.13+-0.13, P is lower then 0.001).
On the other hand, transgenic SHR compared to SHR controls showed significantly reduced infarct size (52.6+-4.3% vs. 72.4+-2.9% of area at risk, P is lower then 0.001). Similar differences were observed in isolated perfused hearts and the increased susceptibility of transgenic SHR to arrhythmias was abolished by reserpine suggesting the involvement of catecholamines.
To further search for possible molecular mechanisms of altered ischemic tolerance, we compared gene expression profiles in left ventricles dissected from 6-week-old transgenic SHR versus age-matched controls using Illumina-based sequencing. Circadian rhythms and oxidative phosphorylation were identified as the top Kegg pathways while circadian rhythms, VDR/RXR activation, IGF1 signaling and HMGB1 signaling were the top IPA canonical pathways potentially important for Cd36-mediated effects on ischemic tolerance.