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Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-?1 pathways.

ABSTRACT: Angiotensin-converting enzyme inhibitors (ACEIs) can improve the fibrotic processes in many internal organs. Recent studies have shown a relationship between ACEI with cutaneous scar formation, although it has not been confirmed, and the underlying mechanism is unclear. In this study, we cultured mouse NIH 3T3 fibroblasts with different concentrations of ACEI. We measured cell proliferation with a Cell Counting Kit-8 and collagen expression with a Sirius Red Collagen Detection Kit. Flow cytometry and western blotting were used to detect transforming growth factor ?1 (TGF-?1) signaling. We also confirmed the potential antifibrotic activity of ACEI in a rat scar model. ACEI reduced fibroblast proliferation, suppressed collagen and TGF-?1 expression, and downregulated the phosphorylation of SMAD2/3 and TAK1, both in vitro and in vivo. A microscopic examination showed that rat scars treated with ramipril or losartan were not only narrower than in the controls, but also displayed enhanced re-epithelialization and neovascularization, and the formation of organized granulation tissue. These data indicate that ACEI inhibits scar formation by suppressing both TGF-?1/SMAD2/3 and TGF-?1/TAK1 pathways, and may have clinical utility in the future.

SUBMITTER: Fang QQ

PROVIDER: S-EPMC5820264 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways.

Fang Qing-Qing QQ Wang Xiao-Feng XF Zhao Wan-Yi WY Ding Shi-Li SL Shi Bang-Hui BH Xia Ying Y Yang Hu H Wu Li-Hong LH Li Cai-Yun CY Tan Wei-Qiang WQ

Scientific reports 20180220 1

Angiotensin-converting enzyme inhibitors (ACEIs) can improve the fibrotic processes in many internal organs. Recent studies have shown a relationship between ACEI with cutaneous scar formation, although it has not been confirmed, and the underlying mechanism is unclear. In this study, we cultured mouse NIH 3T3 fibroblasts with different concentrations of ACEI. We measured cell proliferation with a Cell Counting Kit-8 and collagen expression with a Sirius Red Collagen Detection Kit. Flow cytometr ...[more]

PMID: 29463869

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Project description:Overactivity of the renin-angiotensin system, oxidative stress, and cyclooxygenases (COX) in the brain are implicated in the pathogenesis of hypertension. We previously reported that angiotensin-converting enzyme 2 (ACE2) overexpression in the brain attenuates the development of deoxycorticosterone acetate-salt hypertension, a neurogenic hypertension model with enhanced brain renin-angiotensin system and sympathetic activity. To elucidate the mechanisms involved, we investigated whether oxidative stress, mitogen-activated protein kinase signaling and cyclooxygenase (COX) activation in the brain are modulated by ACE2 in neurogenic hypertension. Deoxycorticosterone acetate-salt hypertension significantly increased expression of Nox-2 (+61±5%), Nox-4 (+50±13%), and nitrotyrosine (+89±32%) and reduced activity of the antioxidant enzymes, catalase (-29±4%) and superoxide dismutase (-31±7%), indicating increased oxidative stress in the brain of nontransgenic mice. This increased oxidative stress was attenuated in transgenic mice overexpressing ACE2 in the brain. Deoxycorticosterone acetate-salt-induced reduction of neuronal nitric oxide synthase expression (-26±7%) and phosphorylated endothelial nitric oxide synthase/total endothelial nitric oxide synthase (-30±3%), and enhanced phosphorylation of protein kinase B and extracellular signal-regulated kinase 1/2 in the paraventricular nucleus, were reversed by ACE2 overexpression. In addition, ACE2 overexpression blunted the hypertension-mediated increase in gene and protein expression of COX-1 and COX-2 in the paraventricular nucleus. Furthermore, gene silencing of either COX-1 or COX-2 in the brain, reduced microglial activation and accompanied neuroinflammation, ultimately attenuating Deoxycorticosterone acetate-salt hypertension. Together, these data provide evidence that brain ACE2 overexpression reduces oxidative stress and COX-mediated neuroinflammation, improves antioxidant and nitric oxide signaling, and thereby attenuates the development of neurogenic hypertension.

Dataset Information

Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-?1 pathways.

Publications

Angiotensin-converting enzyme inhibitor reduces scar formation by inhibiting both canonical and noncanonical TGF-β1 pathways.

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