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Progerin impairs vascular smooth muscle cell growth via the DNA damage response pathway.

ABSTRACT: Mutations of the lamin A gene cause various premature aging syndromes, including Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner syndrome. In HGPS (but not atypical Werner syndrome), extensive loss of vascular smooth muscle cells leads to myocardial infarction with premature death. The underlying mechanisms how single gene mutations can cause various phenotypes are largely unknown. We performed an interactome analysis using mutant forms of lamin A involved in progeroid syndromes. We found that the mutant lamin A responsible for HGPS, known as progerin, could not bind to proteins related to the DNA damage response, including DNA-dependent protein kinase (DNA-PK). In contrast, wild-type lamin A and lamin A mutants causing atypical Werner syndrome were able to bind to these molecules. We also found that forced expression of progerin in vascular smooth muscle cells led to activation of DNA-PK and cellular growth arrest, while knockdown of DNA-PK attenuated this. Deletion of p53 also improved the inhibition of cell growth due to forced expression of progerin. These findings suggested that progerin activates the DNA damage response pathway and that dysregulation of this pathway may be responsible for the development of cardiovascular pathology in patients with HGPS.

SUBMITTER: Kinoshita D

PROVIDER: S-EPMC5470950 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Progerin impairs vascular smooth muscle cell growth via the DNA damage response pathway.

Kinoshita Daisuke D Nagasawa Ayako A Shimizu Ippei I Ito Takashi K TK Yoshida Yohko Y Tsuchida Masanori M Iwama Atsushi A Hayano Toshiya T Minamino Tohru T

Oncotarget 20170501 21

Mutations of the lamin A gene cause various premature aging syndromes, including Hutchinson-Gilford progeria syndrome (HGPS) and atypical Werner syndrome. In HGPS (but not atypical Werner syndrome), extensive loss of vascular smooth muscle cells leads to myocardial infarction with premature death. The underlying mechanisms how single gene mutations can cause various phenotypes are largely unknown. We performed an interactome analysis using mutant forms of lamin A involved in progeroid syndromes. ...[more]

PMID: 28423660

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Project description:Persistently unrepaired DNA damage has been identified as a causative factor for vascular ageing. We have previously shown that a defect in the function or expression of the DNA repair endonuclease ERCC1 (excision repair cross complement 1) in mice leads to accelerated, nonatherosclerotic ageing of the vascular system from as early as 8 weeks after birth. Removal of ERCC1 from endothelial alone partly explains this ageing, as shown in endothelial-specific Ercc1 knockout mice. In this study, we determined vascular ageing due to DNA damage in vascular smooth muscle cells, as achieved by smooth muscle-selective genetic removal of ERCC1 DNA repair in mice (SMC-KO: SM22αCre+ Ercc1fl/-). Vascular ageing features in SMC-KO and their wild-type littermates (WT: SM22αCre+ Ercc1fl/+) were examined at the age of 14 weeks and 25 weeks. Both SMC-KO and WT mice were normotensive. Compared to WT, SMC-KO showed a reduced heart rate, fractional shortening, and cardiac output. SMC-KO showed progressive features of nonatherosclerotic vascular ageing as they aged from 14 to 25 weeks. Decreased subcutaneous microvascular dilatation and increased carotid artery stiffness were observed. Vasodilator responses measured in aortic rings in organ baths showed decreased endothelium-dependent and endothelium-independent responses, mostly due to decreased NO-cGMP signaling. NADPH oxidase 2 and phosphodiesterase 1 inhibition improved dilations. SMC-KO mice showed elevated levels of various cytokines that indicate a balance shift in pro- and anti-inflammatory pathways. In conclusion, SMC-KO mice showed a progressive vascular ageing phenotype in resistant and conduit arteries that is associated with cardiac remodeling and contractile dysfunction. The changes induced by DNA damage might be limited to VSMC but eventually affect EC-mediated responses. The fact that NADPH oxidase 2 as wells as phosphodiesterase 1 inhibition restores vasodilation suggests that both decreased NO bioavailability and cGMP degradation play a role in local vascular smooth muscle cell ageing induced by DNA damage.

Project description:BACKGROUND:Atherosclerotic plaques demonstrate extensive accumulation of oxidative DNA damage, predominantly as 8-oxoguanine (8oxoG) lesions. 8oxoG is repaired by base excision repair enzymes; however, the mechanisms regulating 8oxoG accumulation in vascular smooth muscle cells (VSMCs) and its effects on their function and in atherosclerosis are unknown. METHODS:We studied levels of 8oxoG and its regulatory enzymes in human atherosclerosis, the mechanisms regulating 8oxoG repair and the base excision repair enzyme 8oxoG DNA glycosylase I (OGG1) in VSMCs in vitro, and the effects of reducing 8oxoG in VSMCs in atherosclerosis in ApoE-/- mice. RESULTS:Human plaque VSMCs showed defective nuclear 8oxoG repair, associated with reduced acetylation of OGG1. OGG1 was a key regulatory enzyme of 8oxoG repair in VSMCs, and its acetylation was crucial to its repair function through regulation of protein stability and expression. p300 and sirtuin 1 were identified as the OGG1 acetyltransferase and deacetylase regulators, respectively, and both proteins interacted with OGG1 and regulated OGG1 acetylation at endogenous levels. However, p300 levels were decreased in human plaque VSMCs and in response to oxidative stress, suggesting that reactive oxygen species-induced regulation of OGG1 acetylation could be caused by reactive oxygen species-induced decrease in p300 expression. We generated mice that express VSMC-restricted OGG1 or an acetylation defective version (SM22?-OGG1 and SM22?-OGG1K-R mice) and crossed them with ApoE-/- mice. We also studied ApoE-/- mice deficient in OGG1 (OGG1-/-). OGG1-/- mice showed increased 8oxoG in vivo and increased atherosclerosis, whereas mice expressing VSMC-specific OGG1 but not the acetylation mutant OGG1K-R showed markedly reduced intracellular 8oxoG and reduced atherosclerosis. VSMC OGG1 reduced telomere 8oxoG accumulation, DNA strand breaks, cell death and senescence after oxidant stress, and activation of proinflammatory pathways. CONCLUSIONS:We identify defective 8oxoG base excision repair in human atherosclerotic plaque VSMCs, OGG1 as a major 8oxoG repair enzyme in VSMCs, and p300/sirtuin 1 as major regulators of OGG1 through acetylation/deacetylation. Reducing oxidative damage by rescuing OGG1 activity reduces plaque development, indicating the detrimental effects of 8oxoG on VSMC function.

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Progerin impairs vascular smooth muscle cell growth via the DNA damage response pathway.

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Progerin impairs vascular smooth muscle cell growth via the DNA damage response pathway.

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