Protective role of vascular smooth muscle cell PPARγ in angiotensin II-induced vascular disease

Marchesi, Chiara; Rehman, Asia; Rautureau, Yohann; Kasal, Daniel A.; Briet, Marie; Leibowitz, Avshalom; Simeone, Stefania; Ebrahimian, Talin; Neves, Mário Fritsch; Offermanns, Stefan; Gonzalez, Frank J.; Paradis, Pierre; Schiffrin, Ernesto L.

doi:10.1093/cvr/cvs362

Cited by 45 publications

(37 citation statements)

References 44 publications

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“…We have previously shown that PPARγ activation blocks OPG-induced up-regulation of ATr1 in human AAA explant and AoSMC [19]. A protective role for PPARγ in aortic aneurysm has recently been demonstrated in two independent mouse models of AAA incorporating vascular smooth muscle cell-selective Pparg deletion [17,43]. Importantly, the absence of vascular smooth muscle cell PPARγ rendered mice more susceptible to CTSS-associated degeneration of medial elastin [17].…”

Section: Discussionmentioning

confidence: 99%

Osteoprotegerin Deficiency Limits Angiotensin II–Induced Aortic Dilatation and Rupture in the Apolipoprotein E–Knockout Mouse

Moran

Jose

Biroš

et al. 2014

ATVB

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Objective Mounting evidence links osteoprotegerin (OPG) with cardiovascular disease. Elevated serum and aortic tissue OPG are associated with the presence and growth of abdominal aortic aneurysm (AAA) in humans, however, a role for OPG in AAA pathogenesis remains to be shown. We examined the functional significance of OPG in aortic aneurysm using an Opg-deficient mouse model and in vitro investigations. Approach/Results Homozygous deletion of Opg in apolipoprotein E-deficient mice (ApoE−/−Opg−/−) inhibited AngII-induced aortic dilatation. Survival free from aortic rupture was increased from 67% in ApoE−/−Opg+/+ controls to 94% in ApoE−/−Opg−/− mice (P=0.040). Serum concentrations of pro-inflammatory cytokines/chemokines, and aortic expression for cathepsin S (CTSS), matrix metalloproteinase (MMP) 2 and MMP9 after seven days (early-phase) AngII infusion were significantly reduced in ApoE−/−Opg−/− mice compared to ApoE−/−Opg+/+ controls. In addition, aortic expression of markers for an inflammatory phenotype in aortic vascular smooth muscle cells (AoSMC) in response to early-phase AngII infusion were significantly lower in Opg-deficient mice. In vitro, human AAA vascular smooth muscle cells (AASMC) produced more CTSS and exhibited increased CTSS-derived elastolytic activity than healthy AoSMC; while recombinant human OPG stimulated CTSS-dependent elastase activity in AoSMC. Conclusions These findings support a role for OPG in aortic aneurysm through up-regulation of CTSS, MMP2, and MMP9 within the aorta, and promoting an inflammatory phenotype in AoSMC in response to AngII.

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Section: Discussionmentioning

confidence: 99%

Osteoprotegerin Deficiency Limits Angiotensin II–Induced Aortic Dilatation and Rupture in the Apolipoprotein E–Knockout Mouse

Moran

Jose

Biroš

et al. 2014

ATVB

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“…15–17 Smooth muscle PPAR-γdeficiency blunts the protective effects of thiazolidinediones on atherosclerosis and augments angiotensin II-induced oxidative stress, inflammation and vascular remodeling. 18,19 Selective vascular smooth muscle interference with PPARγ causes a loss of NO-responsiveness, an increase in vasoconstriction and hypertension. 4 …”

Section: Discussionmentioning

confidence: 99%

Interference With Peroxisome Proliferator-Activated Receptor-γ in Vascular Smooth Muscle Causes Baroreflex Impairment and Autonomic Dysfunction

et al. 2014

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S-P467L mice expressing dominant negative Peroxisome Proliferator Activated Receptor-γ selectively in vascular smooth muscle, exhibit impaired vasodilation, augmented vasoconstriction, hypertension and tachycardia. We hypothesized that tachycardia in S-P467L mice is due to baroreflex dysfunction. S-P467L mice displayed increased sympathetic traffic to the heart and decreased baroreflex gain and effectiveness. Carotid arteries exhibited inward remodeling but no changes in distensibility or stress/strain. Aortic depressor nerve activity in response to increased arterial pressure was blunted in S-P467L mice. However, the arterial pressure and heart rate responses to aortic depressor nerve stimulation were unaltered in S-P467L mice suggesting the central and efferent limbs of the baroreflex arc remain intact. There was no transgene expression in nodose ganglion, and no change in expression of the acid-sensing ion channel-2 or -3 in nodose ganglion. There was a trend for decreased expression of transient receptor potential vanilloid-1 receptor mRNA in nodose ganglion, but no difference in the immunochemical staining of transient receptor potential vanilloid-1 receptor in the termination area of the left aortic depressor nerve in S-P467L mice. Although there was no difference in the maximal calcium response to capsaicin in cultured nodose neurons from S-P467L mice, there was decreased desensitization of transient receptor potential vanilloid-1 receptor channels. In conclusion, S-P467L mice exhibit baroreflex dysfunction due to a defect in the afferent limb of the baroreflex arc caused by impaired vascular function, altered vascular structure, or compromised neurovascular coupling. These findings implicate vascular smooth muscle Peroxisome Proliferator Activated Receptor-γ as a critical determinant of neurovascular signaling.

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“…Thus, PPARγ agonist inhibits AngII-induced PKCζ activation, ERK1/2 activation, Krueppel-like factor 5 expression and VSMC proliferation (168). In addition, enhanced AngII-induced vascular remodeling, contractility, inflammation and endothelial dysfunction are observed in inducible vascular smooth muscle-specific PPARγ deficient mice, which seems to involve oxidative stress due to decreased expression of SOD3 (169). Interestingly, it was also shown that endothelial-specific expression of dominant negative PPARγ (V290M) exhibited endothelial dysfunction and an augmented pressor response to AngII (170).…”

Section: Tissue-specific Roles Of At1 Receptor and Transcriptionalmentioning

confidence: 99%

AT1 receptor signaling pathways in the cardiovascular system

Kawai

Forrester

O’Brien

et al. 2017

Pharmacological Research

165

114

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The importance of the renin angiotensin aldosterone system in cardiovascular physiology and pathophysiology has been well described whereas the detailed molecular mechanisms remain elusive. The angiotensin II type 1 receptor (AT1 receptor) is one of the key players in the renin angiotensin aldosterone system. The AT1 receptor promotes various intracellular signaling pathways resulting in hypertension, endothelial dysfunction, vascular remodeling and end organ damage. Accumulating evidence shows the complex picture of AT1 receptor-mediated signaling; AT1 receptor-mediated heterotrimeric G protein-dependent signaling, transactivation of growth factor receptors, NADPH oxidase and ROS signaling, G protein-independent signaling, including the β-arrestin signals and interaction with several AT1 receptor interacting proteins. In addition, there is functional cross-talk between the AT1 receptor signaling pathway and other signaling pathways. In this review, we will summarize an up to date overview of essential AT1 receptor signaling events and their functional significances in the cardiovascular system.

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Protective role of vascular smooth muscle cell PPARγ in angiotensin II-induced vascular disease

Abstract: Inducible Pparγ inactivation in VSMCs exacerbated Ang II-induced vascular remodelling and endothelial dysfunction via enhanced vascular oxidative stress and inflammation, revealing the protective role of VSMC PPARγ in angiotensin II-induced vascular injury.

Cited by 45 publications

References 44 publications

Osteoprotegerin Deficiency Limits Angiotensin II–Induced Aortic Dilatation and Rupture in the Apolipoprotein E–Knockout Mouse

Osteoprotegerin Deficiency Limits Angiotensin II–Induced Aortic Dilatation and Rupture in the Apolipoprotein E–Knockout Mouse

Interference With Peroxisome Proliferator-Activated Receptor-γ in Vascular Smooth Muscle Causes Baroreflex Impairment and Autonomic Dysfunction

AT1 receptor signaling pathways in the cardiovascular system

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