Analysis of coding sequences for tissue inhibitor of metalloproteinases 1 (TIMP1) and 2 (TIMP2) in patients with aneurysms
Introduction
Rupture of an abdominal aortic (AAA) or intracranial (IA) aneurysm is a significant cause of mortality and morbidity, and 1–6% of the population in the USA and other industrialized countries harbor aneurysms (see Verloes et al., 1996). Despite the major advances in surgical treatment, the survival rate after a ruptured aneurysm is low. Early diagnosis of aneurysms is, therefore, important. If it were possible to predict who is at risk for developing an aneurysm, diagnostic efforts (ultrasonography, computerized tomography and magnetic resonance imaging) could be directed towards those at risk.
Familial predisposition to both AAAs and IAs is now well recognized (see Verloes et al., 1996; Ronkainen et al., 1997). The possible genetic factors involved in the development of aneurysms include (see Verloes et al., 1996): (a) structural components of arteries; (b) enzymes degrading the structural molecules; and (c) inhibitors of the proteolytic process. DNA sequencing of 50 aortic aneurysm patients (Tromp et al., 1993) and 55 IA or carotid artery dissection patients (Kuivaniemi et al., 1993) revealed that mutations in type III procollagen are an infrequent cause of aneurysms.
The development of aneurysms is associated with remodeling of the extracellular matrix, including breakdown of structural components of the vascular wall (see Verloes et al., 1996). Collagenase activity and production of 92-kDa gelatinase (MMP9) are increased in ruptured aneurysmal aorta (see Verloes et al., 1996). The increased proteolytic activity could be due to overexpression of the enzymes or down-regulation of their inhibitors. In fact, decreased levels of tissue inhibitors of metalloproteinases (TIMPs) in AAAs have been reported (see Verloes et al., 1996). Furthermore, the ratio of matrix metalloproteinase (MMP) mRNA amount to TIMP mRNA was higher in AAA than in normal aortas (Tamarina et al., 1997). The relative TIMP deficiency could be due to local tissue conditions inhibiting the expression or mutations in the primary structure of the TIMP genes. There are at least four members in the TIMP family, all of which were cloned, sequenced and mapped onto human chromosomes (see Olson et al., 1998).
We studied the coding sequences of TIMP1 and TIMP2 in patients with AAA and/or IA to determine whether mutations in the TIMP genes are associated with aneurysms.
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Materials and methods
This study was initiated at Thomas Jefferson University and was approved by the Institutional Review Committees of Thomas Jefferson University and Wayne State University School of Medicine. Skin biopsies obtained after written informed consent were used to establish fibroblast cultures. RNA was isolated, cDNA synthesized, PCR products purified and genomic DNA isolated as described previously (Tromp et al., 1993). Oligonucleotide primers based on the cDNA sequences of TIMP1 (TIMP1-I,
Results and discussion
To investigate the possibility that aneurysms are caused by defects in the genes for TIMP1 or TIMP2, the sequences of the coding regions of TIMP1 and TIMP2 were determined in 19 unrelated individuals (12 had AAA, one had AAA and IA, four had IA, and two were clinically unaffected). All except one of the 17 aneurysm patients had a family history for the disease. The type III procollagen cDNA sequences in all of these individuals were normal (Kuivaniemi et al., 1993; Tromp et al., 1993).
The
Acknowledgements
This work was supported by grants from the National Institutes of Health (HL 45996) and the American Heart Association, Michigan Affiliate, and by funds from the Wayne State University School of Medicine.
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