Laboratory of Molecular and Genetic Cardiovascular Pathophysiology

Madrid, Spain

Laboratory of Molecular and Genetic Cardiovascular Pathophysiology

Madrid, Spain
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Fuster J.J.,Laboratory of Molecular and Genetic Cardiovascular Pathophysiology | Gonzalez-Navarro H.,Institute Biomedicina Of Valencia | Gonzalez-Navarro H.,Fundacion Investigacion Hospital Clinico Of Valencia | Vinue A.,Institute Biomedicina Of Valencia | And 9 more authors.
Arteriosclerosis, Thrombosis, and Vascular Biology | Year: 2011

Objective-: Genetic ablation of the growth suppressor p27 Kip1 (p27) in the mouse aggravates atherosclerosis coinciding with enhanced arterial cell proliferation. However, it is unknown whether molecular mechanisms that limit p27's protective function contribute to atherosclerosis development and whether p27 exerts proliferation-independent activities in the arterial wall. This study aims to provide insight into both questions by investigating the role in atherosclerosis of p27 phosphorylation at serine 10 (p27-phospho-Ser10), a major posttranslational modification of this protein. Methods and Results-: Immunoblotting studies revealed a marked reduction in p27-phospho-Ser10 in atherosclerotic arteries from apolipoprotein E-null mice, and expression of the nonphosphorylatable mutant p27Ser10Ala, either global or restricted to bone marrow, accelerated atherosclerosis. p27Ser10Ala expression did not affect cell proliferation in early and advanced atheroma but activated RhoA/Rho-associated coiled-coil containing protein kinase (ROCK) signaling and promoted macrophage foam cell formation in a ROCK-dependent manner. Supporting the clinical relevance of these findings, human atherosclerotic coronary arteries exhibited a prominent reduction in p27-phospho-Ser10 and increased ezrin/radixin/moesin protein phosphorylation, a marker of RhoA/ROCK activation. Conclusion-: Scarce phosphorylation of p27 at Ser10 is a hallmark of human and mouse atherosclerosis and promotes disease progression in mice. This proatherogenic effect is mediated by a proliferation-independent mechanism that involves augmented foam cell formation owing to increased RhoA/ROCK activity. These findings unveil a new atheroprotective action of p27 and identify p27-phospho-Ser10 as an attractive target for the treatment of atherosclerosis. © 2011 American Heart Association. All rights reserved.


Gonzalez J.M.,Institute Biomedicina Of Valencia | Gonzalez J.M.,Laboratory of Molecular and Genetic Cardiovascular Pathophysiology | Pla D.,Institute Biomedicina Of Valencia | Perez-Sala D.,CSIC - Biological Research Center | Andres V.,Laboratory of Molecular and Genetic Cardiovascular Pathophysiology
Frontiers in Bioscience - Scholar | Year: 2011

Lamin A and lamin C (A-type lamins, both encoded by the LMNA gene) are major components of the mammalian nuclear lamina, a complex proteinaceous structure that acts as a scaffold for protein complexes that regulate nuclear structure and function. Abnormal accumulation of farnesylated-progerin, a mutant form of prelamin A, plays a key role in the pathogenesis of the Hutchinson-Gilford progeria syndrome (HGPS), a devastating disorder that causes the death of affected children at an average age of 13.5 years, predominantly from premature atherosclerosis and myocardial infarction or stroke. Remarkably, progerin is also present in normal cells and appears to progressively accumulate during aging of non-HGPS cells. Therefore, understanding how this mutant form of lamin A provokes HGPS may shed significant insight into physiological aging. In this review, we discuss recent advances into the pathogenic mechanisms underlying HGPS, the main murine models of the disease, and the therapeutic strategies developed in cellular and animal models with the aim of reducing the accumulation of farnesylated-progerin, as well as their use in clinical trials of HGPS.


Trigueros-Motos L.,Laboratory of Molecular and Genetic Cardiovascular Pathophysiology | Gonzalez J.M.,Laboratory of Molecular and Genetic Cardiovascular Pathophysiology | Gonzalez J.M.,Institute Biomedicina Of Valencia | Rivera J.,Laboratory of Molecular and Genetic Cardiovascular Pathophysiology | Andres V.,Laboratory of Molecular and Genetic Cardiovascular Pathophysiology
Frontiers in Bioscience - Scholar | Year: 2011

Hutchinson-Gilford Progeria Syndrome (HGPS), a rare human disease characterized by premature aging, is mainly caused by the abnormal accumulation of progerin, a mutant form of the mammalian nuclear envelope component lamin A. HGPS patients exhibit vascular alterations and die at an average age of 13 years, predominantly from myocardial infarction or stroke. Animal models of HGPS have been a valuable tool in the study of the pathological processes implicated in the origin of this disease and its associated cardiovascular alterations. Some of the molecular mechanisms of HGPS might be relevant to the process of normal aging, since progerin is detected in cells from normal elderly humans. Conversely, processes linked to normal aging, such as the increase in oxidative stress, might be relevant to the pathogenic mechanisms of HGPS. In this review, we discuss recent advances in the understanding of the molecular mechanisms underlying the cardiovascular alterations associated with HGPS, the potential role of oxidative stress, and therapeutic approaches for the treatment of this devastating disease.

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