Peroxisome Proliferator-activated Receptor γ Induces Apoptosis and Inhibits Autophagy of Human Monocyte-derived Macrophages via Induction of Cathepsin L

Abstract

Macrophages play a pivotal role in the pathophysiology of atherosclerosis. These cells express cathepsin L (CatL), a cysteine protease that has been implicated in atherogenesis and the associated arterial remodeling. In addition, macrophages highly express peroxisome proliferator-activated receptor (PPAR) ␥, a transcription factor that regulates numerous genes important for lipid and lipoprotein metabolism, for glucose homeostasis, and inflammation. Hence, PPAR␥ might affect macrophage function in the context of chronic inflammation such as atherogenesis. In the present study, we examined the effect of PPAR␥ activation on the expression of CatL in human monocyte-derived macrophages (HMDM). Activation of PPAR␥ by the specific agonist GW929 concentration-dependently increased the levels of CatL mRNA and protein in HMDM. By promoter analysis, we identified a functional PPAR response element-like sequence that positively regulates CatL expression. In addition, we found that PPAR␥-induced CatL promotes the degradation of Bcl2 without affecting Bax protein levels. Consistently, degradation of Bcl2 could be prevented by a specific CatL inhibitor, confirming the causative role of CatL. PPAR␥-induced CatL was found to decrease autophagy through reduction of beclin 1 and LC3 protein levels. The reduction of these proteins involved in autophagic cell death was antagonized either by the CatL inhibitor or by CatL knockdown. In conclusion, our data show that PPAR␥ can specifically induce CatL, a proatherogenic protease, in HMDM. In turn, CatL inhibits autophagy and induces apoptosis. Thus, the proatherogenic effect of CatL could be neutralized by apoptosis, a beneficial phenomenon, at least in the early stages of atherosclerosis.

Acute spinal cord injury in rats should target activated autophagy

“…18 Cell death is subdivided into 3 types: apoptosis (Type I), autophagic cell death (Type II), and necrosis (Type III). 35 Apoptosis is the principal mechanism by which cells are physiologically eliminated in metazoan organisms. 15 Autophagy is a double-edged sword in cell survival and cell death.…”

“…Previous studies have shown that bcl-2 family members are dual regulators of apoptosis and autophagy. 5,21,31,35,58 Beclin1, a marker of autophagy, is a bcl-2-binding protein. Nu- trient starvation, which is a potent physiological inducer of autophagy, can stimulate the dissociation of beclin1 from its inhibitors, either by activating BH3-only proteins (such as Bad) or by posttranslational modifications (such as phosphorylation) of Bcl2 that may reduce its affinity for beclin 1 and BH3-only proteins.…”

Apolipoprotein E receptor-2 deficiency enhances macrophage susceptibility to lipid accumulation and cell death to augment atherosclerotic plaque progression and necrosis

“…One mechanism that leads to p53 phosphorylation and stabilization is through activation of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) [33, 35, 36]. Analysis of PPARγ mRNA levels by qPCR showed elevated PPARγ-encoding Pparg mRNA expression in apoER2-deficient RAW 264.7 cells compared to control cells (Fig.…”

Possible Pivotal Role of Latent Chronic T. gondii Infection in the Pathogenesis of Atherosclerosis

“…Lipoprotein modification and uptake by atherosclerotic lesion cells, mainly macrophages and VSMCs, are important pathological steps in the formation of atherosclerotic plaques [669,673,675,677,[680][681][682][683] . CatL [680,684,685] and CatB [686,687] expression is enhanced in human coronary atherosclerotic lesions, carotid lesions, and in abdominal aortic aneurysms [676] . CatB, CatL and CatD, were found in macrophage-derived foam cells in lipid-rich plaque areas [688,689] .…”