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Improving vagal activity ameliorates cardiac fibrosis induced by angiotensin II: in vivo and in vitro.

ABSTRACT: Cardiac remodeling is characterized by overactivity of the renin-angiotensin system (RAS) and withdrawal of vagal activity. We hypothesized that improving vagal activity could attenuate cardiac fibrosis induced by angiotensin II (Ang II) in vivo and in vitro. Rats were subjected to abdominal aorta constriction (AAC) with or without pyridostigmine (PYR) (31 mg/kg/d). After 8 weeks, PYR significantly decreased Ang II level, AT1 protein expression, and collagen deposition in cardiac tissue and improved heart rate variability, baroreflex sensitivity and cardiac function, which were abolished by atropine. In vitro, treatment of cardiac fibroblasts (CFs) with Ang II (10(-7) M) increased cell proliferation, migration, transformation, and secretory properties, which were significantly diminished by acetylcholine (ACh, 10(-6) M). Subsequently, Ang II significantly increased collagen type I expression as well as metalloproteinase (MMP)-2 expression and activity. Transforming growth factor (TGF)-β1 expression and Smad3 phosphorylation presented a similar trend. Notably, the knockdown of the acetylcholine M2 receptor by siRNA could abolish ACh anti-fibrotic action. These data implicated cholinesterase inhibitor can increase vagal activity and reduce local Ang II level, and ACh inhibit Ang II pro-fibrotic effects. Our findings suggested that the parasympathetic nervous system can serve as a promising target for cardiac remodeling treatment.

SUBMITTER: Liu JJ

PROVIDER: S-EPMC4656999 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Low-intensity pulsed ultrasound ameliorates angiotensin II-induced cardiac fibrosis by alleviating inflammation via a caveolin-1-dependent pathway.

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Monocytic fibroblast precursors mediate fibrosis in angiotensin-II-induced cardiac hypertrophy.

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MicroRNA-503 promotes angiotensin II-induced cardiac fibrosis by targeting Apelin-13.

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Fibroblast-specific IKK-β deficiency ameliorates angiotensin II-induced adverse cardiac remodeling in mice.

Project description:Cardiac inflammation and fibrosis contribute significantly to hypertension-related adverse cardiac remodeling. IκB kinase β (IKK-β), a central coordinator of inflammation through activation of NF-κB, has been demonstrated as a key molecular link between inflammation and cardiovascular disease. However, the cell-specific contribution of IKK-β signaling toward adverse cardiac remodeling remains elusive. Cardiac fibroblasts are one of the most populous nonmyocyte cell types in the heart that play a key role in mediating cardiac fibrosis and remodeling. To investigate the function of fibroblast IKK-β, we generated inducible fibroblast-specific IKK-β-deficient mice. Here, we report an important role of IKK-β in the regulation of fibroblast functions and cardiac remodeling. Fibroblast-specific IKK-β-deficient male mice were protected from angiotensin II-induced cardiac hypertrophy, fibrosis, and macrophage infiltration. Ablation of fibroblast IKK-β inhibited angiotensin II-stimulated fibroblast proinflammatory and profibrogenic responses, leading to ameliorated cardiac remodeling and improved cardiac function in IKK-β-deficient mice. Findings from this study establish fibroblast IKK-β as a key factor regulating cardiac fibrosis and function in hypertension-related cardiac remodeling.

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IRX2 regulates angiotensin II-induced cardiac fibrosis by transcriptionally activating Egr1 in mice

Project description:This SuperSeries is composed of the SubSeries listed below.

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Fimasartan, an angiotensin II receptor antagonist, ameliorates an in vivo zebrafish model of heart failure.

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| S-EPMC7652659 | biostudies-literature

Overexpression of peptidase inhibitor 16 attenuates angiotensin II-induced cardiac fibrosis via regulating HDAC1 of cardiac fibroblasts.

Project description:Cardiac hypertrophy and fibrosis are the major causes of heart failure due to non-ischaemia heart disease. To date, no specific therapy exists for cardiac fibrosis due to the largely unknown mechanisms of disease and lack of applicable therapeutic targets. In this study, we aimed to explore the role and associated mechanism of peptidase inhibitor 16 (PI16) in cardiac fibrosis induced by angiotensin II. In cardiac fibroblasts (CFs), overexpressed PI16 significantly inhibited CF proliferation and the levels of fibrosis-associated proteins. Further analysis of epigenetic changes in CF revealed that overexpressed PI16 decreases the nuclear level of histone deacetylase 1 (HDAC1) after angiotensin II treatment, resulting in increased histone 3 acetylation in K18 and K27 lysine. However, overexpression of HDAC1 by an adenovirus vector in CFs reversed these changes. Echocardiography showed that PI16 transgenic (Tg) mice have smaller left ventricle mass than wild-type mice. Histological analysis data showed that PI16 Tg mice demonstrated smaller cardiomyocyte size and less collagen deposition than wild-type mice. The effects of PI16 on HDAC1 and histone 3 were also confirmed in PI16 Tg mice using immunostaining. Generally, PI16 is a HDAC1 regulator specifically in CFs, and PI16 overexpression prevents cardiac hypertrophy and fibrosis by inhibiting stress-induced CF activation.

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