The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: a systematic review and meta-analysis

Morris, Dylan; Biroš, Erik; Cronin, Oliver; Kuivaniemi, Helena; Golledge, Jonathan

doi:10.1136/heartjnl-2013-304129

Cited by 60 publications

(53 citation statements)

References 33 publications

(34 reference statements)

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“…The meta-analysis of 8 SNPs selected from the studies in which 58 SNPs within MMPs and TIMPs were investigated in abdominal aortic aneurism (AAA) pinpoint the significant association of only MMP-3 rs3025058 with AAA presence [115]. Another one, published the same year, which was investigated several genes in AAA presented the similar results for MMP-3 rs3025058 [116].…”

Section: Mmp-3supporting

confidence: 54%

Overview of MMP Biology and Gene Associations in Human Diseases

Djurić¹,

Živković²

2017

The Role of Matrix Metalloproteinase in Human Body Pathologies

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Interactions of cell with the extracellular matrix (ECM) are crucial for normal development and functioning of the human organism. By regulating ECM integrity and composition matrix metalloproteinases (MMPs) play the main role in ECM molecules signaling and influence processes such as proliferation, migration, differentiation and apoptosis.ECM remodeling is a highly regulated process. When imbalanced it could contribute to pathophysiology of many diseases. The MMPs actions and activity are regulated through different mechanisms such as regulation of transcription, activation of latent MMPs, inhibition of MMP function by tissue inhibitors of metalloproteinases. MMPs are a family of calcium-and zinc-dependent endoproteinase, which share similar structural domains, but differs in substrate specificity, cell localizations and inducibility. Genetic variations in MMPs have been associated with a number of diseases, still not all findings are reproducible. Nine of 23 human genes encoding MMPs are located in a cluster on chromosome 11, which implicate their haplotype-driven effects. They could be important mediators of disease severity and could trigger acute events. In this chapter, we will review the basics of MMP biology and the most significant associations of MMPs variations with cardiovascular and neurological diseases in humans and MMPs therapeutic potential through synthetic inhibitors.

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Section: Mmp-3supporting

confidence: 54%

Overview of MMP Biology and Gene Associations in Human Diseases

Djurić¹,

Živković²

2017

The Role of Matrix Metalloproteinase in Human Body Pathologies

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“…They have identified various associations of some significance, but the vast majority of the studies included have analysed populations of less than 150 individuals. Further meta-analyses of gene-association studies have identified positive associations for the following SNPs: MMP-3 rs3025058,33 MMP-2 rs243865,34 MMP-13 rs2252070,34 elastin rs2071307,34 C reactive protein rs3091244,35TGF β rs764522 and rs1036095 36. A recent meta-analysis (in press) from our group has not confirmed previously identified putative associations for the ACE inhibitors rs3025058, MMP-3 rs3025058, nitric oxide synthase rs1799752 and methylenetetrahydrofolate reductase rs1801133 SNPs 37.…”

Section: Genetic Studiesmentioning

confidence: 99%

The genetic basis for aortic aneurysmal disease

Saratzis

Bown

2014

Heart

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Aortic aneurysms are an important cause of cardiovascular death in elderly patients. At present, little is known of the pathobiology of aneurysmal disease and this limits the ability to develop non-surgical treatments to stabilise aneurysms. Both thoracic and abdominal aortic aneurysms (AAA) demonstrate a strong genetic component in their aetiology. Determination of the genetic variants associated with aneurysmal disease is one approach to increasing the understanding the pathways leading to aneurysmal degeneration of the aorta. In this review, we aim to summarise the current knowledge of the genetics underlying the two most common disease phenotypes, thoracic aortic aneurysm (TAA) and AAA. Genetically, AAA represent a multifactorial disease, with the likelihood that there are multiple variants of very low effect sizes contributing to the overall genetic disease risk. Non-syndromic TAA appears to be associated with a smaller number of risk loci with higher individual effect sizes at these loci. Candidate gene and genome-wide approaches have identified robust associations between AAA and variants in/nearby the SORT1, low-density lipoprotein receptor, DAB2IP, LRP1, ELN, CRP, TGFB and various matrix metallo-proteinase genes suggesting that aberrations of lipid metabolism and proteolytic pathways are the key contributors to disease. Some of these associations (eg, LRP1) are not associated with atherosclerosis, suggesting pathways unique to AAA. Genetic variants associated with non-syndromic TAA (ACTA2 and MYH11) are related to the TGFβ pathway, strongly implicated in syndromic TAA, thus suggesting a common pathway between syndromic and non-syndromic TAA.

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“…Molecular imaging targeted at the determinants of AAA expansion and rupture appears particularly promising in this regard (2). Matrix metalloproteinase (MMP) activation is a main pathophysiologic feature of AAA and is believed to be closely related to aneurysm progression and risk of rupture (3,4). Accordingly, molecular imaging of MMP activation may be a useful tool for AAA risk stratification.…”

mentioning

confidence: 99%

Preclinical Evaluation of RYM1, a Matrix Metalloproteinase–Targeted Tracer for Imaging Aneurysm

Toczek

Gona

et al. 2017

J Nucl Med

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Matrix metalloproteinases (MMPs) play a key role in abdominal aortic aneurysm (AAA) development. Accordingly, MMP-targeted imaging provides important information regarding vessel wall biology in the course of aneurysm development. Given the small size of the vessel wall and its proximity with blood, molecular imaging of aneurysm optimally requires highly sensitive tracers with rapid blood clearance. To this end, we developed a novel hydrosoluble zwitterionic MMP inhibitor, RYM, on the basis of which a pan-MMP tracer, RYM1, was designed. Here, we describe the development and preclinical evaluation of RYM1 in comparison with RP805, a commonly used pan-MMP tracer in murine models of aneurysm. Methods: The macrocyclic hydroxamate-based pan-MMP inhibitor coupled with 6-hydrazinonicotinamide, RYM1, was synthesized and labeled with 99m Tc. Radiochemical stability of 99m Tc-RYM1 was evaluated by radio-high-performance liquid chromatography analysis. Tracer blood kinetics and biodistribution were compared with 99m Tc-RP805 in C57BL/6J mice (n 5 10). 99m Tc-RYM1 binding to aneurysm and specificity were evaluated by quantitative autoradiography in apolipoprotein E-deficient (apoE 2/2 ) mice with CaCl 2 -induced carotid aneurysm (n 5 11). Angiotensin II-infused apoE 2/2 (n 5 16) mice were used for small-animal SPECT/CT imaging. Aortic tissue MMP activity and macrophage marker CD68 expression were assessed by zymography and reverse-transcription polymerase chain reaction. Results: RYM1 showed nanomolar range inhibition constants for several MMPs. 99m Tc-RYM1 was radiochemically stable in mouse blood for 5 h and demonstrated rapid renal clearance and lower blood levels in vivo compared with 99m Tc-RP805. 99m Tc-RYM1 binding to aneurysm and its specificity were shown by autoradiography in carotid aneurysm. Angiotensin II infusion in apoE 2/2 mice for 4 wk resulted in AAA formation in 36% (4/11) of surviving animals. In vivo 99m Tc-RYM1 small-animal SPECT/ CT images showed higher uptake of the tracer in AAA than nondilated aortae. Finally, aortic uptake of 99m Tc-RYM1 in vivo correlated with aortic MMP activity and CD68 expression. Conclusion: The newly developed pan-MMP inhibitor-based tracer 99m Tc-RYM1 displays favorable pharmacokinetics for early vascular imaging and enables specific detection of inflammation and MMP activity in aneurysm. Abdomi nal aortic aneurysm (AAA) accounts for 10,000-15,000 recorded deaths, mainly due to rupture, in the United States each year. Current clinical guidelines for surgical repair of AAA are based on aneurysm size, expansion rate, and clinical symptoms (1). However, a significant portion of AAA ruptures occurs in patients who do not meet the criteria for AAA repair, and some large AAAs may remain stable for many years. As such, new risk-stratification tools are needed to overcome the limitations of the current approach to patient selection for AAA repair. Molecular imaging targeted at the determinants of AAA expansion and rupture appears particularly promising in this regard (2). Matrix me...

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The association of genetic variants of matrix metalloproteinases with abdominal aortic aneurysm: a systematic review and meta-analysis

Abstract: A common SNP within the MMP3 promoter region, previously suggested to increase MMP3 expression, appears to be a moderate risk factor for AAA.

Cited by 60 publications

References 33 publications

Overview of MMP Biology and Gene Associations in Human Diseases

Overview of MMP Biology and Gene Associations in Human Diseases

The genetic basis for aortic aneurysmal disease

Preclinical Evaluation of RYM1, a Matrix Metalloproteinase–Targeted Tracer for Imaging Aneurysm

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