Molecular Genetics of Vascular Disease

National Human Genome Research Institute

Investigators

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Abstract

Our laboratory is interested in the molecular genetics of vascular diseases. We utilize several approaches, including molecular and cellular biology studies, genetic studies in mice, and clinical investigations in patients with vascular diseases. Our focus is on the genetics and genomics of vascular remodeling during common, complex cardiovascular diseases and during premature aging syndromes.[unreadable] [unreadable] Vascular proliferative diseases are characterized by smooth muscle cell (VSMC) proliferation and migration. KIS (kinase interacting with stathmin) targets two key regulators of cell proliferation and migration, the cyclin-dependent kinase inhibitor p27Kip1 and the microtubule destabilizing protein stathmin. Phosphorylation of p27Kip1 by KIS leads to cell-cycle progression, whereas the target sequence and the physiological relevance of stathmin phosphorylation by KIS in VSMCs are unknown. Vascular wound repair in KIS-/- mice results in accelerated neointima formation, which is composed predominantly of VSMCs. Deletion of KIS led to increased migratory activity of VSMCs accompanied by increased cytoplasmic tubulin destabilizing activity, whereas proliferation of VSMCs was abolished due to delayed nuclear export and degradation of p27Kip1. This pro-migratory phenotype was the result of increased stathmin protein levels due to a lack of stathmin phosphorylation by KIS at serine 38 and diminished stathmin protein degradation. Down-regulation of stathmin in KIS-/- VSMCs fully restored the phenotype, and stathmin-/- mice demonstrated normal responses to vascular injury. These data suggest that KIS protects against excessive neointima formation by stathmin-mediated inhibition of VSMC migration and that VSMC migration represents a major mechanism of vascular wound repair, constituting a relevant target and mechanism for therapeutic interventions.[unreadable] [unreadable] We are continuing a genome-wide association study of a vascular disease, termed in-stent restenosis (ISR), in order to understand the potential genetic contribution. ISR is an example of a human cardiovascular disease characterized by abnormal vascular remodeling. We are using a case-control approach to analyze genotypes collected from multiple clinical US sites. Our goal is to identify genomic profiles of patients with ISR in order to better diagnose and triage patients undergoing these procedures and to potentially refine therapeutics.[unreadable] [unreadable] Finally, we have collaborated with the Francis Collins lab on investigations of the premature aging syndrome, Hutchinson-Gilford Progeria Syndrome. HGPS is a dramatic form of human premature aging in which death occurs at a mean age of 13, usually from heart attack or stroke. Almost all cases of HGPS are caused by a de novo point mutation in the lamin A gene that results in production of a mutant lamin A protein, termed progerin which in turn is permanently modified by a lipid farnesyl group, and acts as a dominant negative, disrupting nuclear structure. Previous work has shown that treatment with farnesyltransferase inhibitors (FTIs) can prevent and even reverse this nuclear abnormality in cultured HGPS fibroblasts. In addition, we have previously created a mouse model of HGPS that shows progressive loss of vascular smooth muscle cells in the media of the large arteries, in a pattern that is strikingly similar to the cardiovascular disease seen in patients with HGPS. New work now demonstrates that the dose-dependent administration of the FTI tipifarnib to this HGPS mouse model can significantly prevent both the onset of the cardiovascular phenotype as well as the late progression of already existing cardiovascular disease.[unreadable] [unreadable] In summary, our studies of the molecular genetics of vascular remodeling have explored p27-KIS signaling pathways, the genomics of ISR, and pathological arterial remodeling in HGPS.