Vasorin deficiency leads to cardiac hypertrophy by targeting MYL7 in young mice

Guo, Xiaoping; Yu, Ping; Liang, Jie; Mo, Zhongxiang; Zhang, Mingyuan; Yang, Liyu; Huang, Xuejing; Hu, Bing; Liu, Jiajuan; Ouyang, Yanling; He, Min

doi:10.1111/jcmm.17034

Cited by 13 publications

(11 citation statements)

References 47 publications

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“…The RNAseq study highlighted the downregulation of the anti-hypertrophic genes Wif1 , Slitrk4 , Sfrp2 and Myl7 in the Ercc1 Δ/− mice treated with sActRIIB. Myl7 has been shown to inhibit cardiac hypertrophy ( Sun et al, 2021 ), whereas Wif1 impacts hypertrophy through inhibition of the Wnt/β-catenin pathway ( Lu et al, 2013 ). Additionally, sActRIIB treatment of Ercc1 Δ/− mouse hearts increased the expression of Fgf6 , which is associated with protein synthesis and muscle hypertrophy ( Xu et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling

Clavere

Alqallaf

Rostron

et al. 2022

Disease Models &Amp; Mechanisms

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In the heart, ageing is associated with DNA damage, oxidative stress, fibrosis and activation of the activin signalling pathway, leading to cardiac dysfunction. The cardiac effects of activin signalling blockade in progeria are unknown. This study investigated the cardiac effects of progeria induced by attenuated levels of Ercc1 required for DNA excision/repair and the impact of activin signalling blockade using a soluble activin receptor type IIB (sActRIIB). DNA damage and oxidative stress were significantly increased in Ercc1Δ/- hearts but were reduced by sActRIIB treatment. sActRIIB treatment improved cardiac systolic function and induced cardiomyocyte hypertrophy in Ercc1Δ/- hearts. RNA-seq analysis showed that in Ercc1Δ/- hearts there was an increase in pro-oxidant and a decrease in antioxidant gene expression, whilst sActRIIB treatment reversed this. Ercc1Δ/- hearts also expressed higher levels of anti-hypertrophic genes and a decrease in pro-hypertrophic ones which were also reversed by sActRIIB treatment. These results show for the first time that inhibition of activin A receptor signalling attenuates cardiac dysfunction, pathological tissue remodelling and gene expression in Ercc1 deficient mice and presents a potentially novel therapeutic target for heart diseases.

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Section: Discussionmentioning

confidence: 99%

Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling

Clavere

Alqallaf

Rostron

et al. 2022

Disease Models &Amp; Mechanisms

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“…In fact, the vascular dysfunction caused by Vasn deletion is mediated by Ang II levels, SMC phenotype switching, and changes in intracellular calcium homeostasis and ECs NO signaling. A recent study suggested that cardiac hypertrophy was the cause of death in Vasn −/− mice (Sun et al, 2022). Our results indicated that the harmful impact of Vasn deletion on vascular function might also contribute to the high observed mortality rate.…”

Section: Discussionmentioning

confidence: 99%

Vasorin plays a critical role in vascular smooth muscle cells and arterial functions

Louvet

Lenglet

Krautzberger

et al. 2022

Journal Cellular Physiology

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Within the cardiovascular system, the protein vasorin (Vasn) is predominantly expressed by vascular smooth muscle cells (VSMCs) in the coronary arteries and the aorta. Vasn knockout (Vasn−/−) mice die within 3 weeks of birth. In the present study, we investigated the role of vascular Vasn expression on vascular function. We used inducible Vasn knockout mice (VasnCRE‐ERT KO and VasnSMMHC‐CRE‐ERT2 KO, in which respectively all cells or SMCs only are targeted) to analyze the consequences of total or selective Vasn loss on vascular function. Furthermore, in vivo effects were investigated in vitro using human VSMCs. The death of VasnCRE‐ERT KO mice 21 days after tamoxifen injection was concomitant with decreases in blood pressure, angiotensin II levels, and vessel contractibility to phenylephrine. The VasnSMMHC‐CRE‐ERT2 KO mice displayed concomitant changes in vessel contractibility in response to phenylephrine and angiotensin II levels. In vitro, VASN deficiency was associated with a shift toward the SMC contractile phenotype, an increase in basal intracellular Ca2+ levels, and a decrease in the SMCs' ability to generate a calcium signal in response to carbachol or phenylephrine. Additionally, impaired endothelium‐dependent relaxation (due to changes in nitric oxide signaling) was observed in all Vasn knockout mice models. Our present findings highlight the role played by Vasn SMC expression in the maintenance of vascular functions. The mechanistic experiments suggested that these effects are mediated by SMC phenotype switching and changes in intracellular calcium homeostasis, angiotensin II levels, and NO signaling.

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“…org/ home/ gene/ VASN). [7][8][9][10][11][12][20][21][22] development. 22 On the contrary, the VASN expression is significantly lower in premature klotho-hypomorphic mice with a short lifespan of 8-9 weeks.…”

Section: Va Sorin Protein E Xpre Ss I On In Arterial Wall S and Vs M C Smentioning

confidence: 99%

“…Recent evidence expands the role of VASN beyond vascular remodeling, implicating it in adverse cardiac remodeling 11 . Indeed, Sun et al reported that VASN knockout mice exhibit markers of myocardial metabolic abnormalities and myocardial injury such as elevated levels of aspartate aminotransferase, homocysteine, and lactate dehydrogenase 11 . The absence of VASN also contributed to increased heart weight and cardiomyocyte size, indicating cardiac hypertrophy 11 .…”

Section: Vasorin In Cardiac Remodeling and Heart Failurementioning

confidence: 99%

“…[2][3][4][5][6] In the aging cardiovascular system, a loss of balance between the pro-fibrotic signaling molecule, transforming growth factor-beta1 (TGF-β1), and the anti-fibrotic signaling molecule Vasorin (VASN), may play a determinant role in the initiation and progression of cardiovascular thickening, collagen deposition, and calcification, prompting age-associated adverse cardiovascular remodeling and triggering age-associated diseases. 4,[7][8][9][10][11] In fact, this imbalance has been shown to significantly contribute to cardiovascular fibrosis and stiffening with advancing age, development, or mechanical and metabolic insults. 4,7,9,10,12 During aging, both TGF-β1 and angiotensin II (Ang II) signaling increase in the cardiovascular system.…”

Section: Introductionmentioning

confidence: 99%

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Enhanced vasorin signaling mitigates adverse cardiovascular remodeling

Wang,

McGraw,

Monticone

et al. 2024

Aging Medicine

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Arterial stiffening is a critical risk factor contributing to the exponential rise in age‐associated cardiovascular disease incidence. This process involves age‐induced arterial proinflammation, collagen deposition, and calcification, which collectively contribute to arterial stiffening. The primary driver of proinflammatory processes leading to collagen deposition in the arterial wall is the transforming growth factor‐beta1 (TGF‐β1) signaling. Activation of this signaling is pivotal in driving vascular extracellular remodeling, eventually leading to arterial fibrosis and calcification. Interestingly, the glycosylated protein vasorin (VASN) physically interacts with TGF‐β1, and functionally restraining its proinflammatory fibrotic signaling in arterial walls and vascular smooth muscle cells (VSMCs). Notably, as age advances, matrix metalloproteinase type II (MMP‐2) is activated, which effectively cleaves VASN protein in both arterial walls and VSMCs. This age‐associated/MMP‐2‐mediated decrease in VASN levels exacerbates TGF‐β1 activation, amplifying arterial fibrosis and calcification in the arterial wall. Importantly, TGF‐β1 is a downstream molecule of the angiotensin II (Ang II) signaling pathway in the arterial wall and VSMCs, which is modulated by VASN. Indeed, chronic administration of Ang II to young rats significantly activates MMP‐2 and diminishes the VASN expression to levels comparable to untreated older control rats. This review highlights and discusses the role played by VASN in mitigating fibrosis and calcification by alleviating TGF‐β1 activation and signaling in arterial walls and VSMCs. Understanding these molecular physical and functional interactions may pave the way for establishing VASN‐based therapeutic strategies to counteract adverse age‐associated cardiovascular remodeling, eventually reducing the risk of cardiovascular diseases.

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Vasorin deficiency leads to cardiac hypertrophy by targeting MYL7 in young mice

Cited by 13 publications

References 47 publications

Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling

Inhibition of activin A receptor signalling attenuates age-related pathological cardiac remodelling

Vasorin plays a critical role in vascular smooth muscle cells and arterial functions

Enhanced vasorin signaling mitigates adverse cardiovascular remodeling

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