Vascular Smooth Muscle Cell-Specific Progerin Expression Provokes Contractile Impairment in a Mouse Model of Hutchinson-Gilford Progeria Syndrome that Is Ameliorated by Nitrite Treatment.

Lara Del Campo,María Jesús Andrés-Manzano,Amanda Sánchez-López,Beatriz Dorado,Vicente Andrés,Cristina González-Gómez

doi:10.3390/cells9030656

Abstract

Cardiovascular disease (CVD) is the main cause of death worldwide, and aging is its leading risk factor. Aging is much accelerated in Hutchinson–Gilford progeria syndrome (HGPS), an ultra-rare genetic disorder provoked by the ubiquitous expression of a mutant protein called progerin. HGPS patients die in their teens, primarily due to cardiovascular complications. The primary causes of age-associated CVD are endothelial dysfunction and dysregulated vascular tone; however, their contribution to progerin-induced CVD remains poorly characterized. In the present study, we found that progeroid LmnaG609G/G609G mice with ubiquitous progerin expression show both endothelial dysfunction and severe contractile impairment. To assess the relative contribution of specific vascular cell types to these anomalies, we examined LmnaLCS/LCSTie2Cretg/+ and LmnaLCS/LCSSm22αCretg/+ mice, which express progerin specifically in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), respectively. Whereas vessel contraction was impaired in mice with VSMC-specific progerin expression, we observed no endothelial dysfunction in mice with progerin expression restricted to VSMCs or ECs. Vascular tone regulation in progeroid mice was ameliorated by dietary sodium nitrite supplementation. Our results identify VSMCs as the main cell type causing contractile impairment in a mouse model of HGPS that is ameliorated by nitrite treatment.

Highlights

Cardiovascular disease (CVD) is the leading cause of death worldwide, in part due to progressive aging, the main CVD risk factor [1]
Vasodilation induced by either acetylcholine or DEA-nitric oxide (NO) was not significantly different from controls in LmnaLCS/Lamin C-Stop” mice (LCS) SM22αCretg/+ (Figure 3B) or LmnaLCS/LCS Tie2Cretg/+ aortic rings (Figure 3D). These results demonstrate that smooth muscle, not endothelium, is the main vascular cell type driving contractile impairment in progeroid mice and suggest that progeroid endothelial dysfunction requires simultaneous expression of progerin in vascular smooth muscle cells (VSMCs) and endothelial cells (ECs)
The Hutchinson–Gilford progeria syndrome (HGPS) mouse models generated over the last decade are excellent tools for studying cardiovascular aging over a relatively short time frame and without the presence of confounding cofactors, enabling the identification of the cell types most susceptible to progerin-induced CVD

Summary

Introduction

Cardiovascular disease (CVD) is the leading cause of death worldwide, in part due to progressive aging, the main CVD risk factor [1]. Studies on the effects of age alone (the only factor we cannot modify or treat) remain scarce due to their high research costs associated with the necessary long-term resource investment and delays in collecting results. The study of premature aging syndromes characterized by accelerated CVD offers a unique opportunity to investigate age-dependent drivers of CVD in the absence of other confounding risk factors [5,6]. Hutchinson–Gilford progeria syndrome (HGPS, OMIM 176670) is a rare genetic disease characterized by accelerated aging and death in adolescence [5,6,7,8,9]. HGPS children have impaired postnatal growth, lipodystrophy, alopecia, pigmented and wrinkled skin, and skeletal dysplasia

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Conclusion