My laboratory has had a 20 year interest in understanding basic and clinical mechanisms underlying maladaptive remodeling in blood vessels. Atherosclerosis, in-stent restenosis, transplant arteriopathy, aneurysm formation, and other blood vessel diseases result from molecular and cellular processes that build over multiple decades; these diseases are the major cause of death and disability in this country. We utilize molecular, cellular, and genetic approaches to investigate the basic mechanisms of vascular remodeling, namely, the role of growth factors and cell cycle proteins in regulating vascular cell proliferation. More recently, we have applied an understanding of these mechanisms to a clinical investigation of the genetic susceptibility to restenosis. Our focus is on the genetics and genomics of vascular remodeling during common, complex cardiovascular diseases and during premature aging syndromes.? ? Through our investigations of the signaling pathways mediated by the cyclin kinase inhibitor, p27, we identified (using a yeast two-hybrid approach) the protein arginine N-methyltransferase, PRMT2. Arginine methylation by PRMT2 is a posttranslational modification important in the regulation of protein signaling, and we have determined PRMT2 effects on diverse cellular functions, including the retinoblastoma gene product (RB), NF-jB and leptin signaling. PRMT2 directly binds and regulates RB through its AdoMet binding domain, and PRMT2 represses E2F transcriptional activity in an RB-dependent manner. Interestingly, PRMT2 inhibits cell activation and promotes cell death through an NF-jB mechanism; that is, PRMT2 blocks nuclear export of IjB-a through a leptomycin-sensitive pathway, increasing nuclear IjB-a and decreasing NF-jB DNA binding. In work in progress, we have determined that PRMT2 is an endogenous regulator of leptin sensitivity through arginine methylation of STAT3.? ? We have also pursued the vascular properties of heme oxygenase, since its expression is upregulated in vascular remodeling and is regulated by the CKIs. Using Hmox-/- mice, we previously found that HO-1 directly reduces vasoconstriction and inhibits cell proliferation, independent of nitric oxide. Since intravascular thrombosis forms at sites of tissue inflammation, we hypothesized further that HO-1 protects against arterial thrombosis during oxidant stress. We have subsequently found that Hmox deficiency accelerates arterial thrombosis through effects on the endothelium, which can be reversed by carbon monoxide inhalation. We detected several mechanisms accounting for this protective effect. First, ECs in Hmox1-/- arteries are more susceptible to apoptosis and denudation, leading to platelet rich micro-thrombi in the subendothelium. Second, arterial tissue factor and plasma von Willebrands Factor are significantly elevated in Hmox1-/- mice, consistent with EC loss. Third, following transplantation of Hmox1-/- donor bone marrow into Hmox1+/+ recipients and subsequent vascular injury, we have observed rapid arterial thrombosis compared to Hmox1+/+ mice receiving Hmox1+/+ BM. Fourth, inhaled carbon monoxide, a by-product of heme metabolism by HO-1, rescues the prothrombotic phenotype in Hmox1-/- mice. Hence, HO-1 has a direct, protective effect against thrombosis during vascular damage, and we have concluded that induction of HO-1 may be beneficial in the prevention of thrombosis associated with vascular oxidant stress and inflammation. ? ? We are continuing work on the genetics and genomics of a common vascular phenotype, in-stent restenosis (ISR), in order to understand the genetic susceptibility of this complex, common cardiovascular disease. We are conducting a case control genome wide association study in approximately 750 cases and 1500 controls utilizing patient samples from multiple cardiac catheterization laboratories. Gene expression profiling is also underway in a subset of patients, and we plan to correlates findings from the GWAS analysis with their gene expression profiles. Extensive phenotypic data has been collected on all patients. 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.? ? Finally, we have collaborated with the Francis Collins lab on investigations of the premature aging syndrome, Hutchinson-Gilford Progeria Syndrome. We have focused on natural history studies in mice and humans as well as potential treatments of HGPS in a mouse model and a human protocol. A mouse model of HGPS (a transgenic line that contains human mutant G608G LMNA gene inserted through a BAC clone) recapitulates the human cardiovascular phenotype. The large arteries in these mice develop a progressive loss of medial VSMCs, spontaneous breaks in elastin structures, and replacement by collagen and proteoglycans as they age; this process is discernible by 5 months of age in the aorta and carotid arteries. By 12 months, these arteries are essentially void of medial VSMCs with extensive collagen and proteoglycan deposition extending into the adventitia, creating a fibrous sheath around a degenerative media. This pathology in mice mimics the vascular disease seen in HGPS individuals, who are typically asymptomatic even while these structural changes are evolving within their arterial system. We have participated in a natural history study of the cardiovascular phenotype in HGPS children conducted in the NIH Clinical Center, under the direction of Dr. William Gaul, NHGRI Clinical Director. This work has nicely characterized the cardiovascular phenotype in HGPS children. Finally, current work focuses on the role of farnesyltransferase inhibitors (FTIs) to prevent the characteristic nuclear abnormalities in HGPS by inhibiting farnesylation of progerin protein. Ongoing studies of FTI treatment of transgenic mice overexpressing progerin will address the potential of FTIs to prevent and reverse the vascular abnormalities. These findings are being translated into a human clinical protocol, lead by Dr. Mark Kieran at the Dana Farber Cancer Institute, with whom we are also collaborating. Our hope is that FTI therapy may prevent and reverse the abnormal vascular remodeling which leads to premature myocardial infarction and stroke.? ? In summary, our studies of the molecular genetics of vascular remodeling have explored cell cycle signaling pathways, the genomics of in-stent restenosis, and the natural history of cardiovascular disease in HGPS.
| Blaisdell, Carol J; Gail, Dorothy B; Nabel, Elizabeth G (2009) National Heart, Lung, and Blood Institute perspective: lung progenitor and stem cells--gaps in knowledge and future opportunities. Stem Cells 27:2263-70 |
| Crook, Martin F; Olive, Michelle; Xue, Hai-Hui et al. (2008) GA-binding protein regulates KIS gene expression, cell migration, and cell cycle progression. FASEB J 22:225-35 |
| Nabel, Elizabeth G (2008) The physician-scientist: a value proposition. J Clin Invest 118:1233-5 |
| Merideth, Melissa A; Gordon, Leslie B; Clauss, Sarah et al. (2008) Phenotype and course of Hutchinson-Gilford progeria syndrome. N Engl J Med 358:592-604 |
| Capell, Brian C; Collins, Francis S; Nabel, Elizabeth G (2007) Mechanisms of cardiovascular disease in accelerated aging syndromes. Circ Res 101:13-26 |
| Kiley, James P; Nabel, Elizabeth G (2007) Treating COPD. N Engl J Med 356:867 |
| Daar, Abdallah S; Singer, Peter A; Persad, Deepa Leah et al. (2007) Grand challenges in chronic non-communicable diseases. Nature 450:494-6 |
| Nabel, Elizabeth G; Shurin, Susan B; Simons-Morton, Denise G et al. (2007) Data and safety monitoring of rosiglitazone trials. Lancet 369:2077 |
| GAIN Collaborative Research Group; Manolio, Teri A; Rodriguez, Laura Lyman et al. (2007) New models of collaboration in genome-wide association studies: the Genetic Association Information Network. Nat Genet 39:1045-51 |
| Nabel, Elizabeth G (2006) The Women's Health Initiative. Science 313:1703 |
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