scholarly journals Genetic reduction of mTOR extends lifespan in a mouse model of Hutchinson‐Gilford Progeria syndrome

Aging Cell ◽  
2021 ◽  
Vol 20 (9) ◽  
Author(s):  
Wayne A. Cabral ◽  
Urraca L. Tavarez ◽  
Indeevar Beeram ◽  
Diana Yeritsyan ◽  
Yoseph D. Boku ◽  
...  
Keyword(s):  
Mouse Model ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals Defective Extracellular Pyrophosphate Metabolism Promotes Vascular Calcification in a Mouse Model of Hutchinson-Gilford Progeria Syndrome That Is Ameliorated on Pyrophosphate Treatment

Circulation ◽  
2013 ◽  
Vol 127 (24) ◽  
pp. 2442-2451 ◽  
Author(s):  
Ricardo Villa-Bellosta ◽  
José Rivera-Torres ◽  
Fernando G. Osorio ◽  
Rebeca Acín-Pérez ◽  
José A. Enriquez ◽  
...  
Keyword(s):  
Mouse Model ◽  
Vascular Calcification ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals Vascular smooth muscle cell‐specific progerin expression in a mouse model of Hutchinson–Gilford progeria syndrome promotes arterial stiffness: Therapeutic effect of dietary nitrite

Aging Cell ◽  
2019 ◽  
Vol 18 (3) ◽  
pp. e12936 ◽  
Author(s):  
Lara del Campo ◽  
Amanda Sánchez‐López ◽  
Mercedes Salaices ◽  
Ryan A. von Kleeck ◽  
Elba Expósito ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Arterial Stiffness ◽  
Mouse Model ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Therapeutic Effect ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals ATP-based therapy prevents vascular calcification and extends longevity in a mouse model of Hutchinson–Gilford progeria syndrome

2019 ◽  
Vol 116 (47) ◽  
pp. 23698-23704 ◽  
Author(s):  
Ricardo Villa-Bellosta
Keyword(s):  
Mouse Model ◽  
Vascular Calcification ◽  
Therapeutic Approach ◽  
Ex Vivo ◽  
Combined Treatment ◽  
Wild Type ◽  
Extended Longevity ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome ◽  
Pyrophosphate Hydrolysis

Pyrophosphate deficiency may explain the excessive vascular calcification found in children with Hutchinson–Gilford progeria syndrome (HGPS) and in a mouse model of this disease. The present study found that hydrolysis products of ATP resulted in a <9% yield of pyrophosphate in wild-type blood and aortas, showing that eNTPD activity (ATP → phosphate) was greater than eNPP activity (ATP → pyrophosphate). Moreover, pyrophosphate synthesis from ATP was reduced and pyrophosphate hydrolysis (via TNAP; pyrophosphate → phosphate) was increased in both aortas and blood obtained from mice with HGPS. The reduced production of pyrophosphate, together with the reduction in plasma ATP, resulted in marked reduction of plasma pyrophosphate. The combination of TNAP inhibitor levamisole and eNTPD inhibitor ARL67156 increased the synthesis and reduced the degradation of pyrophosphate in aortas and blood ex vivo, suggesting that these combined inhibitors could represent a therapeutic approach for this devastating progeroid syndrome. Treatment with ATP prevented vascular calcification in HGPS mice but did not extend longevity. By contrast, combined treatment with ATP, levamisole, and ARL67156 prevented vascular calcification and extended longevity by 12% in HGPS mice. These findings suggest a therapeutic approach for children with HGPS.

scholarly journals 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

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 656 ◽  
Author(s):  
Lara del Campo ◽  
Amanda Sánchez-López ◽  
Cristina González-Gómez ◽  
María Jesús Andrés-Manzano ◽  
Beatriz Dorado ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Mouse Model ◽  
Vascular Smooth Muscle ◽  
Vascular Tone ◽  
Genetic Disorder ◽  
Cell Types ◽  
Dietary Sodium ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

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.

scholarly journals Premature Vascular Aging with Features of Plaque Vulnerability in an Atheroprone Mouse Model of Hutchinson–Gilford Progeria Syndrome with Ldlr Deficiency

Cells ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 2252
Author(s):  
Rosa M. Nevado ◽  
Magda R. Hamczyk ◽  
Pilar Gonzalo ◽  
María Jesús Andrés-Manzano ◽  
Vicente Andrés
Keyword(s):  
Smooth Muscle ◽  
Mouse Model ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Genetic Diseases ◽  
Nuclear Lamina ◽  
Reduced Body ◽  
Unstable Plaques ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Hutchinson–Gilford progeria syndrome (HGPS) is among the most devastating of the laminopathies, rare genetic diseases caused by mutations in genes encoding nuclear lamina proteins. HGPS patients age prematurely and die in adolescence, typically of atherosclerosis-associated complications. The mechanisms of HGPS-related atherosclerosis are not fully understood due to the scarcity of patient-derived samples and the availability of only one atheroprone mouse model of the disease. Here, we generated a new atherosusceptible model of HGPS by crossing progeroid LmnaG609G/G609G mice, which carry a disease-causing mutation in the Lmna gene, with Ldlr−/− mice, a commonly used preclinical atherosclerosis model. Ldlr−/−LmnaG609G/G609G mice aged prematurely and had reduced body weight and survival. Compared with control mice, Ldlr−/−LmnaG609G/G609G mouse aortas showed a higher atherosclerosis burden and structural abnormalities typical of HGPS patients, including vascular smooth muscle cell depletion in the media, adventitial thickening, and elastin structure alterations. Atheromas of Ldlr−/−LmnaG609G/G609G mice had features of unstable plaques, including the presence of erythrocytes and iron deposits and reduced smooth muscle cell and collagen content. Ldlr−/−LmnaG609G/G609G mice faithfully recapitulate vascular features found in patients and thus provide a new tool for studying the mechanisms of HGPS-related atherosclerosis and for testing therapies.

scholarly journals Lonafarnib improves cardiovascular function and survival in a mouse model of Hutchinson-Gilford Progeria Syndrome

2021 ◽  
Author(s):  
Sae-Il Murtada ◽  
Nicole Mikush ◽  
Molly Wang ◽  
Pengwei Ren ◽  
Yuki Kawamura ◽  
...  
Keyword(s):  
Mouse Model ◽  
Premature Death ◽  
Left Ventricular Diastolic Function ◽  
Detailed Examination ◽  
Left Ventricular ◽  
Arterial Structure ◽  
End Stage ◽  
And Function ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

Clinical trials have demonstrated that lonafarnib, a farnesyltransferase inhibitor, extends lifespan in patients afflicted by Hutchinson-Gilford progeria syndrome, a devastating condition that accelerates many characteristics of aging and results in premature death due to cardiovascular sequelae. The US Food and Drug Administration approved ZokinvyTM (lonafarnib) in November 2020 for treating these patients, yet a detailed examination of drug-associated effects on cardiovascular structure, properties, and function has remained wanting. In this paper, we report encouraging outcomes of daily post-weaning treatment with lonafarnib on the composition and biomechanical phenotype of elastic and muscular arteries as well as associated cardiac function in a well-accepted mouse model of progeria that exhibits severe end-stage cardiovascular disease. Lonafarnib resulted in 100% survival of the treated progeria mice to the study end-point (time of 50% survival of untreated mice), with associated improvements in arterial structure and function working together to significantly reduce pulse wave velocity and improve left ventricular diastolic function. By contrast, dual treatment with lonafarnib and rapamycin did not improve outcomes over that achieved with lonafarnib monotherapy.

scholarly journals Vascular Smooth Muscle–Specific Progerin Expression Accelerates Atherosclerosis and Death in a Mouse Model of Hutchinson-Gilford Progeria Syndrome

Circulation ◽  
2018 ◽  
Vol 138 (3) ◽  
pp. 266-282 ◽  
Author(s):  
Magda R. Hamczyk ◽  
Ricardo Villa-Bellosta ◽  
Pilar Gonzalo ◽  
María J. Andrés-Manzano ◽  
Paula Nogales ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Mouse Model ◽  
Vascular Smooth Muscle ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome

scholarly journals Nuclear membrane ruptures underlie the vascular pathology in a mouse model of Hutchinson-Gilford progeria syndrome

JCI Insight ◽  
2021 ◽  
Vol 6 (16) ◽  
Author(s):  
Paul H. Kim ◽  
Natalie Y. Chen ◽  
Patrick J. Heizer ◽  
Yiping Tu ◽  
Thomas A. Weston ◽  
...  
Keyword(s):  
Mouse Model ◽  
Nuclear Membrane ◽  
Vascular Pathology ◽  
Progeria Syndrome ◽  
Hutchinson Gilford Progeria Syndrome
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