Vascular smooth muscle cell-specific progerin expression in a mouse model of Hutchinson–Gilford progeria syndrome promotes arterial stiffness: Therapeutic effect of dietary nitrite
EntityUAM. Departamento de Farmacología
10.1111/acel.12936Aging Cell 18.3 (2019): e12936
Funded byThis study was supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCIU, grants SAF2016‐79490‐R and SAF2016‐80305‐P), with co‐funding from the European Regional Development Fund (ERDF, “Una manera de hacer Europa”). RvK and RKA are supported by NIH grants AG047373, T32‐GM008076, F31HL142160 and NSF grant CMMI 1548571. L.d.C. was supported by a Jordi Soler postdoctoral grant from the Red de Investigación Cardiovascular (RETIC Program, Instituto de Salud Carlos III), and A.S.‐L. was supported by a Severo Ochoa predoctoral grant from the MCIU (SVP‐2014‐068334) and by a grant from Asociación Apadrina la Ciencia‐Ford España‐Ford Motor Company Fund. The CNIC is supported by the MCIU and the Pro‐CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV‐2015‐0505)
ProjectGobierno de España. SAF2016‐79490‐R; Gobierno de España. SAF2016‐80305‐P
Subjectsaging; dietary nitrite; progeria; smooth muscle cells; vascular stiffness; Medicina
Rights© 2019 The Authors
Esta obra está bajo una Licencia Creative Commons Atribución 4.0 Internacional.
Vascular stiffness is a major cause of cardiovascular disease during normal aging and in Hutchinson–Gilford progeria syndrome (HGPS), a rare genetic disorder caused by ubiquitous progerin expression. This mutant form of lamin A causes premature aging associated with cardiovascular alterations that lead to death at an average age of 14.6 years. We investigated the mechanisms underlying vessel stiffness in LmnaG609G/G609G mice with ubiquitous progerin expression, and tested the effect of treatment with nitrites. We also bred LmnaLCS/LCSTie2Cre+/tgand LmnaLCS/LCSSM22αCre+/tg mice, which express progerin specifically in endothelial cells (ECs) and in vascular smooth muscle cells (VSMCs), respectively, to determine the specific contribution of each cell type to vascular pathology. We found vessel stiffness and inward remodeling in arteries of LmnaG609G/G609G and LmnaLCS/LCSSM22αCre+/tg, but not in those from LmnaLCS/LCSTie2Cre+/tgmice. Structural alterations in aortas of progeroid mice were associated with decreased smooth muscle tissue content, increased collagen deposition, and decreased transverse waving of elastin layers in the media. Functional studies identified collagen (unlike elastin and the cytoskeleton) as an underlying cause of aortic stiffness in progeroid mice. Consistent with this, we found increased deposition of collagens III, IV, V, and XII in the media of progeroid aortas. Vessel stiffness and inward remodeling in progeroid mice were prevented by adding sodium nitrite in drinking water. In conclusion, LmnaG609G/G609G arteries exhibit stiffness and inward remodeling, mainly due to progerin-induced damage to VSMCs, which causes increased deposition of medial collagen and a secondary alteration in elastin structure. Treatment with nitrites prevents vascular stiffness in progeria
Google Scholar:del Campo, Lara - Sánchez-López, Amanda - Salaices Sánchez, Mercedes - von Kleeck, Ryan A. - Expósito, Elba - González-Gómez, Cristina - Cussó, Lorena - Guzmán-Martínez, Gabriela - Ruiz-Cabello, Jesús - Desco, Manuel - Assoian, Richard K. - Briones Alonso, Ana María - Andrés, Vicente
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