Pioglitazone Ameliorates Smooth Muscle Cell Proliferation in Cuff-Induced Neointimal Formation by Both Adiponectin-Dependent and -Independent Pathways

Abstract

The aim of this study is to elucidate to what degree adiponectin is involved in TZD-mediated amelioration of neointimal formation. We investigated the effect of 3- or 8-weeks’ pioglitazone on cuff-induced neointimal formation in adiponectin-deficient (APN-KO) and wild-type (WT) mice. Pioglitazone for 3 weeks reduced neointimal formation in the WT mice with upregulation of the plasma adiponectin levels, but failed to reduce neointimal formation in the APN-KO mice, suggesting that pioglitazone suppressed neointimal formation by adiponectin-dependent mechanisms. Pioglitazone for 3 weeks suppressed vascular smooth muscle cell (VSMC) proliferation and increased AdipoR2 expression in the WT mice. In vitro, globular adiponectin activated AMPK through both AdipoR1 and AdipoR2, resulting in the inhibition of VSMC proliferation. Interestingly, 8-weeks’ pioglitazone was reduced neointimal formation in APN-KO mice to degree similar to that seen in the WT mice, suggesting that pioglitazone can also suppress neointimal formation via a mechanism independent of adiponectin. Pioglitazone for 8 weeks completely abrogated the increased VSMC proliferation, along with a reduction of cyclin B1 and cyclin D1 expressions and cardiovascular risk profile in the APN-KO mice. In vitro, pioglitazone suppressed these expressions, leading to inhibition of VSMC proliferation. Pioglitazone suppresses neointimal formation via both adiponectin-dependent and adiponectin-independent mechanisms.

Targeting smooth muscle cell phenotypic switching in vascular disease

“… 130 , 132 TZDs exert antiproliferative, antiplatelet, and anti-inflammatory effects and promote VSMC differentiation ( Fig 5 ). PPAR-γ agonists decrease intimal hyperplasia after PCI, 133 , 134 and vascular PPAR-γ expression was strongly repressed after arterial stenting in minipigs. Systemic rosiglitazone treatment rescued both PPAR-γ and contractile protein expression after stenting and decreased inflammation.…”

In praise of pioglitazone: An economically efficacious therapy for type 2 diabetes and other manifestations of the metabolic syndrome

“…32 In 42 patients with type 2 diabetes and coronary artery disease (CAD), a randomized, double-blind, placebo-controlled, parallel study that utilized photoplethysmographic pulse wave analysis showed that endothelial function was severely impaired in both groups at baseline, but after 12 weeks was significantly improved in the pioglitazone group (Δ reflection index 6.5% ± 5.1% vs. 1.6% ± 2.9%; P = .002). 33 More importantly, in patients with type 2 diabetes, following implantation of zotarolimus-eluting stents, significant neointimal hyperplasia occurred in the stented lesion and the attenuated total atherosclerotic burden was increased. As assessed by intravascular ultrasonography (IVUS) before and after 8 months in the 47 patients randomized to pioglitazone, the increases in neointimal hyperplasia and total atherosclerotic burden were attenuated compared with 47 patients randomized to placebo.…”

“…• Deceleration of the increase in carotid intimal-media thickness 33 • Increased luminar area of coronary arteries 35 Cardiovascular events…”

“…In 42 patients with type 2 diabetes and coronary artery disease (CAD), a randomized, double‐blind, placebo‐controlled, parallel study that utilized photoplethysmographic pulse wave analysis showed that endothelial function was severely impaired in both groups at baseline, but after 12 weeks was significantly improved in the pioglitazone group (Δ reflection index 6.5% ± 5.1% vs. 1.6% ± 2.9%; P = .002) 33 …”

Pulmonary Hypertension and Obesity: Focus on Adiponectin

“…Analogously, the administration of adenovirus-adiponectin into the tail veins of mice exposed to hypoxia improves hypoxia-induced pulmonary arterial remodeling [ 84 ]. Additional therapeutic approaches include: Thiazolidinediones (such as pioglitazone and troglitazone) and synthetic ligands of PPARγ that lead, indirectly, to an increment in production and secretion of adiponectin resulting in the suppression of PASMC proliferation [ 85 ]. In the same way, fenofibrate, a PPARγ agonist, ameliorates endothelial functions by reducing levels of inflammation and increasing adiponectin [ 86 , 87 ].…”