Dataset Information

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.

SUBMITTER: Kubota T

PROVIDER: S-EPMC5050439 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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

Kubota Tetsuya T Kubota Naoto N Sato Hiroyuki H Inoue Mariko M Kumagai Hiroki H Iwamura Tomokatsu T Takamoto Iseki I Kobayashi Tsuneo T Moroi Masao M Terauchi Yasuo Y Tobe Kazuyuki K Ueki Kohjiro K Kadowaki Takashi T

Scientific reports 20161005

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 sup ...[more]

PMID: 27703271

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Project description:Objective- Dysregulated proliferation of vascular smooth muscle cells (VSMC) plays an essential role in neointimal hyperplasia. CD36 functions critically in atherogenesis and thrombosis. We hypothesize that CD36 regulates VSMC proliferation and contributes to the development of obstructive vascular diseases. Approach and Results- We found by immunofluorescent staining that CD36 was highly expressed in human vessels with obstructive diseases. Using guidewire-induced carotid artery injury and shear stress-induced intima thickening models, we compared neointimal hyperplasia in Apoe-/-, Cd36-/- /Apoe-/-, and CD36 specifically deleted in VSMC (VSMC cd36-/-) mice. CD36 deficiency, either global or VSMC-specific, dramatically reduced injury-induced neointimal thickening. Correspondingly, carotid artery blood flow was significantly increased in Cd36-/- /Apoe-/- compared with Apoe-/- mice. In cultured VSMCs from thoracic aorta of wild-type and Cd36-/- mice, we found that loss of CD36 significantly decreased serum-stimulated proliferation and increased cell populations in S phase, suggesting that CD36 is necessary for VSMC S/G2-M-phase transition. Treatment of VSMCs with a TSR (thrombospondin type 1 repeat) peptide significantly increased wild-type, but not Cd36-/- VSMC proliferation. TSR or serum treatment significantly increased cyclin A expression in wild-type, but not in Cd36-/- VSMCs. STAT3 (signal transducer and activator of transcription), which reportedly enhances both VSMC differentiation and maturation, was higher in Cd36-/- VSMCs. CD36 deficiency significantly decreased expression of Col1A1 (type 1 collagen A1 chain) and TGF-?1 (transforming growth factor beta 1), and increased expression of contractile proteins, including calponin 1 and smooth muscle ? actin, and dramatically increased cell contraction. Conclusions- CD36 promotes VSMC proliferation via upregulation of cyclin A expression that contributes to the development of neointimal hyperplasia, collagen deposition, and obstructive vascular diseases.

Project description:BackgroundThe pathophysiology of diabetic retinopathy (DR) is multifaced. A low level of circulating adiponectin (APN) in type 2 diabetes is associated with microvasculature complications, and its role in the evolution of DR is complex.AimThis study is designed to explore the potential impact of APN in the pathogenesis of DR, linking the changes in cellular and biological processes with the pathways, networks, and regulators involved in its actions.MethodsHuman microvascular retinal endothelial cells (HMRECs) were exposed to 30mM glucose (HG) and treated with globular adiponectin (30μg/mL) for 24 hours. The cells were evaluated for reactive oxidative stress (ROS) and apoptosis. RT-PCR profile arrays were utilized to evaluate the profile of genes involved in endothelial functions, angiogenesis, extracellular matrix, and adhesion molecules for hyperglycemic HMRECs treated with adiponectin. In addition, the barrier function, leukocyte migration, and angiogenesis were evaluated. The differential expressed genes (DEGs) were outlined, and bioinformatic analysis was applied.ResultsAdiponectin suppresses ROS production and apoptosis in HMRECs under HG conditions. Adiponectin improved migration and barrier functions in hyperglycemic cells. The bioinformatic analysis highlighted that the signaling pathways of integrin, HMGB1, and p38 AMPK, are mainly involved in the actions of APN on HMRECs. APN significantly affects molecular functions, including the adhesion of cells, chemotaxis, migration of WBCs, and angiogenesis. STAT3, NFKB, IKBKB, and mir-8 are the top upstream regulators, which affect the expressions of the genes of the data set, while TNF and TGFB1 are the top regulators.ConclusionAdiponectin significantly counteracts hyperglycemia at various cellular and molecular levels, reducing its impact on the pathophysiological progression towards DR in vitro using HMRECs. Adiponectin ameliorates inflammatory response, oxidative stress, and endothelial barrier dysfunction using a causal network of NFBk complex, TNF, and HMGB1 and integrin pathways.

Project description:Injury-induced stenosis is a serious vascular complication. We previously reported that p38? (MAPK14), a redox-regulated p38MAPK family member was a negative regulator of the VSMC contractile phenotype in vitro. Here we evaluated the function of VSMC-MAPK14 in vivo in injury-induced neointima hyperplasia and the underlying mechanism using an inducible SMC-MAPK14 knockout mouse line (iSMC-MAPK14-/-). We show that MAPK14 expression and activity were induced in VSMCs after carotid artery ligation injury in mice and ex vivo cultured human saphenous veins. While the vasculature from iSMC-MAPK14-/- mice was indistinguishable from wildtype littermate controls at baseline, these mice exhibited reduced neointima formation following carotid artery ligation injury. Concomitantly, there was an increased VSMC contractile protein expression in the injured vessels and a decrease in proliferating cells. Blockade of MAPK14 through a selective inhibitor suppressed, while activation of MAPK14 by forced expression of an upstream MAPK14 kinase promoted VSMC proliferation in cultured VSMCs. Genome wide RNA array combined with VSMC lineage tracing studies uncovered that vascular injury evoked robust inflammatory responses including the activation of proinflammatory gene expression and accumulation of CD45 positive inflammatory cells, which were attenuated in iSMC-MAPK14-/- mice. Using multiple pharmacological and molecular approaches to manipulate MAPK14 pathway, we further confirmed the critical role of MAPK14 in activating proinflammatory gene expression in cultured VSMCs, which occurs in a p65/NFkB-dependent pathway. Finally, we found that NOX4 contributes to MAPK14 suppression of the VSMC contractile phenotype. Our results revealed that VSMC-MAPK14 is required for injury-induced neointima formation, likely through suppressing VSMC differentiation and promoting VSMC proliferation and inflammation. Our study will provide mechanistic insights into therapeutic strategies for mitigation of vascular stenosis.

Dataset Information

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

Publications

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

Similar Datasets

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