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Interruption of Autophagosome Formation in Cardiovascular Disease, an Evidence for Protective Response of Autophagy

ABSTRACT Background: A heart attack occurs when coronary artery blockage interrupts the blood supply to the heart such as is seen in cardiovascular disease (CVD). Importantly, autophagy is commonly regarded as a host defense mechanism against microbial invaders. Methods: A total of 50 blood samples were obtained from cardiovascular (CV) patients in addition to 30 samples that were obtained from healthy individuals and served as controls. Macrophages were isolated in vitro and propagated from the blood samples. Autophagosome formation, cytokine secretion, and apolipoprotein B (ApoB) gene expression were monitored in patient samples and their derived macrophages. Results: The results showed that autophagy-related (Atg) LC3 and Atg5 genes were significantly down-regulated in all samples obtained from CV patients. Furthermore, the relative gene expression of ApoB, which plays the major role in lipoprotein metabolism, was significantly increased in CV patients. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were increased in these blood samples. Interestingly, targeting of ApoB by small interference RNA (siRNA) reduced the production levels of low-density lipoprotein (LDL), IL-6 and TNF-α in patient-derived macrophages. Further, treatment of patient-derived macrophages with rapamycin, an autophagy inducer agent, successfully regulated the production of LDL, IL-6, TNF-α, and ApoB expression via activation of autophagosome formation. Conclusion: The current data reveal the potential disturbance of autophagy in CV patients that accompanied ApoB over-expression. Furthermore, our findings provide evidence for the protective role of autophagy in accumulation of pro-inflammatory cytokines and intracellular LDL degradation in CV patient-derived macrophages.