Pioglitazone Attenuates Drug-Eluting Stent-Induced Proinflammatory State in Patients by Blocking Ubiquitination of PPAR

Abstract

The inflammatory response after polymer-based drug-eluting stent (DES) placement has recently emerged as a major concern. The biologic roles of peroxisome proliferator-activated receptor-γ (PPAR-γ) activators thiazolidinedione (TZD) remain controversial in cardiovascular disease. Herein, we investigated the antiinflammatory effects of pioglitazone (PIO) on circulating peripheral blood mononuclear cells (MNCs) in patients after coronary DES implantation. Methods and Results. Twenty-eight patients with coronary artery disease and who underwent DES implantations were randomly assigned to pioglitazone (30 mg/d; PIO) or placebo (control; Con) treatment in addition to optimal standard therapy. After 12 weeks of treatment, plasma concentrations of high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and matrix metalloproteinase-9 (MMP-9) were significantly decreased in PIO group compared to the Con group (P = 0.035, 0.011, 0.008, and 0.012, resp.). DES-induced mRNA expressions of IL-6, TNF-α, and MMP-9 in circulating MNC were significantly blocked by PIO (P = 0.031, 0.012, and 0.007, resp.). In addition, PIO markedly inhibited DES-enhanced NF-κB function and DES-blocked PPAR-γ activity. Mechanically, DES induced PPAR-γ ubiquitination and degradation in protein level, which can be totally reversed by PIO. Conclusion. PIO treatment attenuated DES-induced PPAR loss, NF-κB activation, and proinflammation, indicating that PIO may have a novel direct protective role in modulating proinflammation in DES era.

Inhibition of neuronal peroxisome proliferator‐activated receptor‐γ attenuates motor function improvement after spinal cord injury in rats

“…Intrathecal pioglitazone increased the protein level of spinal PPARγ compared to the vehicle group when it was injected in the early phase after SCI. According to previous studies, pioglitazone can increase mRNA levels of PPARγ in cardiomyocytes (Legchenko et al, 2018) and decrease PPARγ ubiquitination in mononuclear cells (Wang et al, 2016). Thus, pioglitazone might have increased the protein level of PPARγ by blocking its protein degradation and enhancing its transcription.…”

PPAR agonists as add-on treatment with metformin in management of type 2 diabetes: a systematic review and meta-analysis

“…For the adequacy of allocation concealment, 3 RCTs (15%) were rated as low risk of bias 22 , 39 , 41 , and 17 (85%) as unclear risk of bias 23 – 25 , 36 – 38 , 40 , 42 – 49 , 51 . For the blinding of participants and personnel, 17 (85%) RCTs were rated as low risk of bias 23 – 25 , 36 – 43 , 46 – 49 , 51 , 52 , 2 (10%) RCTs as high risk and 1 (5%) as unclear risk of bias 44 , 45 . For the blinding of outcomes assessors, 16 (80%) RCTs were rated as low risk of bias 23 – 25 , 36 – 43 , 46 , 47 , 49 , 51 , 52 , 1 (5%) as high risk 45 , and 3 (15%) as unclear risk of bias 22 , 44 , 48 .…”

Stent‐mediated gene and drug delivery for cardiovascular disease and cancer: A brief insight

“…Additional placebo‐controlled clinical studies on drugs administered to treat atherothrombotic disease or in DES‐treated coronary artery disease patients should add to our knowledge with respect to refining the existing drug therapy and idenitifying ways of evading pro‐inflammatory responses in patients post‐stent implantation. A good example is recent study by Wang et al examining the anti‐inflammatory effects of pioglitazone in patients after coronary DES placement.…”