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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:250.)
© 2006 American Heart Association, Inc.

Brief Reviews

Smoking, Metalloproteinases, and Vascular Disease

Todd S. Perlstein; Richard T. Lee

From the Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Cambridge, Mass.

Correspondence to Richard T. Lee, Cardiovascular Research Laboratories, Partners Research Facility, 65 Landsdowne St., Room 279, Cambridge, MA 02139. E-mail rlee{at}rics.bwh.harvard.edu

	Abstract

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
Smoking causes up to 11% of total global cardiovascular deaths. Smoking has numerous effects that may promote atherosclerosis through vascular inflammation and oxidative stress, but the pathogenesis of smoking-related cardiovascular disease remains incompletely understood. The matrix metalloproteinases, a family of endopeptidases that can degrade extracellular matrix components in both physiological and pathophysiological states, play an important role in smoking-associated chronic obstructive pulmonary disease, the second leading cause of smoking attributable mortality. Emerging evidence indicates that the matrix metalloproteinases may also contribute to smoking-related vascular disease. Here we discuss the potential relationship between smoking, matrix metalloproteinases, and acceleration of vascular disease.

The matrix metalloproteinases are emerging as strong candidate mediators of smoking-associated vascular disease. Smoking-induced inflammation and oxidative stress may increase metalloproteinase transcription, increase pro-enzyme activation, and limit endogenous inhibition of metalloproteinase activity. The relationship between smoking, metalloproteinases, and vascular disease is discussed in this brief review.

Key Words: vascular disease • smoking • metalloproteinases

	Introduction

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
In the year 2000, smoking caused an estimated 1.69 million cardiovascular deaths in the world, 11% of total global cardiovascular deaths.¹ Vasomotor dysfunction, alterations in thrombosis/fibrinolysis, and modification of lipids may mediate smoking-related vascular disease, with a central role of vascular inflammation and oxidative stress.² The pathogenesis of smoking-related cardiovascular disease remains incompletely understood. The matrix metalloproteinases, a family of endopeptidases best known for degrading extracellular matrix components in both physiological and pathophysiological states, play an important role in smoking-associated chronic obstructive pulmonary disease, the second leading cause of smoking attributable mortality.^1,3,4 Recent observations suggest that the matrix metalloproteinases may also play an important role in smoking-related vascular disease.

See cover

	Epidemiology of Smoking-Associated Vascular Disease

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
There are an estimated 1 billion smokers in the world.⁵ Cigarette smoking independently increases the risk for coronary atherosclerotic disease, cerebrovascular disease, and peripheral vascular disease.⁶ In a recent multinational case-control study of first myocardial infarction, smoking contributed 36% of the population attributable risk, and the risk of myocardial infarction increased linearly with increasing number of cigarettes smoked.⁷ The relationship between cigarette smoking and risk for stroke is also strong, with an estimated 30% of strokes attributable to smoking in a large prospective cohort study.⁸ The association of smoking with aneurysmal subarachnoid hemorrhage appears particularly strong.^9,10 In a population study of 126 196 subjects, the excess prevalence associated with smoking accounted for 75% of all abdominal aortic aneurysms >4.0 cm.¹¹ The excess prevalence associated with smoking accounted for 76% of the risk for claudication in a case-control study.¹² In a systematic review including 17 studies, smoking increased the risk of symptomatic peripheral arterial disease by 2.6-fold.¹³ The association of smoking with peripheral atherosclerotic disease appears to be stronger than that with coronary atherosclerotic disease or atherosclerotic cerebral vascular disease.⁶ In an analysis of 10 studies including >3 million subjects, the association of smoking with aortic aneurysmal disease was 2.5-times greater than that with coronary disease and 3.5-times greater than that with cerebral vascular disease.¹⁴ It is important to note that the association between cigarette smoke exposure and cardiovascular disease extends to passive smoke exposure, with second-hand smoke increasing the risk for death from ischemic heart disease by one-quarter among nonsmokers.¹⁵

	Smoking-Related Vascular Inflammation and Oxidative Stress

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
Inflammation and arterial wall oxidative stress are central in the pathogenesis of atherosclerosis.^16–18 The ability of cigarette smoke to induce vascular inflammation and oxidative stress appears fundamental to the broad effects of smoking on vascular pathophysiology.² Smokers have higher circulating leukocyte counts and increased circulating markers of inflammation including C-reactive protein, interleukin (IL)-6, soluble intercellular adhesion molecule type 1, E-selectin, and P-selectin^19–21. Urinary excretion of 8-epi-prostaglandin (PG) F2 alpha, a stable product of lipid peroxidation in vivo, is increased in smokers and significantly lessened by vitamin C therapy.²² Cigarette smoke extract markedly increases endothelial superoxide production by NADPH oxidase.²³ Tobacco smoke condensate increases endothelial cell xanthine oxidase transcription and activity.²⁴ Hamsters exposed to cigarette smoke have increased xanthine oxidase activity that is ameliorated by coadministration of superoxide dismutase, suggesting a key role for smoke-induced superoxide.²⁵ Human endothelial cells exposed to sera from smokers have decreased nitric oxide availability despite increased nitric oxide synthase expression, with scavenging of nitric oxide by increased reactive oxygen species generation.^26,27 Smoking-associated endothelial dysfunction can be ameliorated by 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor therapy independently of changes in lipid levels,²⁸ by supplementation with tetrahydrobiopterin,²⁶ and by xanthine oxidase inhibition with allopurinol.²⁹ Monocytes isolated from smokers demonstrate increased adherence to endothelial cells, which is corrected by vitamin C therapy.³⁰ The ability of sera collected from smokers to increase monocyte adherence to endothelial cells is ameliorated by coincubation with L-arginine.³¹ Cigarette smokers have increased autoantibody titers to oxidized low-density lipoprotein (LDL),³² and cigarette smoke extract causes oxidative modification of plasma LDL, an effect ameliorated by vitamin C.³³ The activation of platelets by sera from smokers can be inhibited in vitro by either catalase or reduced glutathione plus peroxidase.³⁴ As discussed, smoking-associated inflammation and oxidative stress may also be responsible for activation of the matrix metalloproteinases.

	Matrix Metalloproteinases

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
The biochemistry of the matrix metalloproteinases has recently been reviewed.³⁵ The matrix metalloproteinases are a family of Zn²⁺-dependent and Ca²⁺-dependent endopeptidases that are best known for the resorption of extracellular matrix components in both normal physiological processes and pathological states. The matrix metalloproteinases can be classified into 6 main groups according to structural similarities and substrate affinities: (1) the collagenases; (2) the gelatinases; (3) the stromelysins; (4) the membrane-type matrix metalloproteinases; (5) the matrilysins; and (6) a heterogenous subgroup. Here we focus on the proteolytic effects of the matrix metalloproteinases; however, it is important to recognize that matrix metalloproteinases act on a broad range of substrates including tumor necrosis factor (TNF) alpha, growth factors and their receptors, plasminogen and its activators, and endothelin.³⁶ Thus, the matrix metalloproteinases should not simply be considered mediators of matrix degradation, despite this historic context. Similarly, the extracellular matrix is not simply an inert scaffold but plays a dynamic role in cellular functions including cell adhesion, migration, apoptosis, growth factors binding, and lipoprotein binding.³⁷

	Matrix Metalloproteinases and Vascular Pathophysiology: Focus on Vascular Remodeling and Plaque Instability

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
Vascular remodeling, which can be defined as any enduring change in the size and/or composition of an adult blood vessel,³⁶ depends on degradation and reorganization of the extracellular matrix, and the participation of the matrix metalloproteinases is essential. Matrix metalloproteinases may disrupt and remodel extracellular matrix barriers allowing vascular smooth muscle cell (VSMC) migration, a key factor in arterial remodeling.³⁸ In addition, extracellular matrix regulates VSMC behavior by sequestering signaling molecules and by acting as contextual ligands for cellular adhesion receptors.³⁹ Monomer collagen stimulates while polymerized collagen inhibits VSMC proliferation via integrin signaling.⁴⁰ Matrix metalloproteinase activity is correlated with VSMC migration and proliferation after vascular injury,^41–43 and inhibition of matrix metalloproteinase activity suppresses VSMC proliferation.^41,44,45 Furthermore, matrix metalloproteinase expression is associated with remodeling of the vascular adventitia.^42,46 Characteristics of unstable plaques susceptible to rupture include a large lipid core, a thin fibrous cap,⁴⁷ and intraplaque hemorrhage.⁴⁸ Matrix metalloproteinases are expressed within atherosclerotic plaques,⁴⁹ particularly at the shoulder regions,⁵⁰ where increased stresses and matrix degradation may combine to rupture the fibrous cap.⁵¹ Matrix metalloproteinases may also contribute atherosclerotic plaque rupture by stimulating neovascularization via generation of angiogenic peptides.^52–54

	Smoking, Matrix Metalloproteinases, and Emphysema

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
The well-described role of matrix metalloproteinases in the pathogenesis of smoking-related chronic obstructive pulmonary disease⁵⁵ serves as a paradigm for considering the potential role of matrix metalloproteinases in smoking-related cardiovascular disease. Cigarette smoke stimulates inflammatory cell recruitment into the lung parenchyma, leading to release of elastolytic proteases that destroy lung extracellular matrix and result in air space enlargement and emphysema.⁵⁵ The matrix metalloproteinases mediate cigarette smoke-induced inflammatory cell recruitment into the lung.^56,57 Matrix metalloproteinases may also participate in cigarette smoke-induced pulmonary vascular remodeling.^58,59 An interesting potential link between the role of matrix metalloproteinases in smoking-induced emphysema and in smoking-induced vascular disease is cadmium. Cadmium, inhaled in cigarette smoke, induces lung proteolysis.⁶⁰ MMP-2 and MMP-9 are increased in a rat model of cadmium-induced emphysema and colocalize with lung parenchyma destruction.⁶¹ Cadmium content of the infrarenal aorta increases in direct proportion to the number of pack-years of cigarettes smoked.⁶² In the NHANES cohort, cadmium exposure partially mediated the effect of smoking on peripheral arterial disease.⁶³ The relationship between cadmium exposure and matrix metalloproteinase activity in the vasculature is unexplored.

	Epidemiology of Smoking-Associated Vascular Disease Suggests a Role of Matrix Metalloproteinases

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
The epidemiology of smoking-related cardiovascular disease suggests that matrix metalloproteinases and matrix degradation may play an important pathophysiological role. Excessive extracellular matrix breakdown is a major determinant of aortic expansion and aneurysm formation.⁶⁴ The association of smoking with aneurysmal subarachnoid hemorrhage may also point to matrix metalloproteinases, as MMP-9 was markedly increased in intracranial aneurysms.⁶⁵ Epidemiological data also implicate smoking in plaque instability. Cigarette smoking predicts premature coronary disease in men and women, hastening the presentation of unstable coronary syndromes by 1 decade.⁶⁶ Among patients with coronary artery disease, cigarette smoking accelerates coronary progression and new lesion formation as assessed by serial quantitative coronary arteriography.⁶⁷ Much of the association of cigarette smoking with acute coronary syndromes appears to be driven by the association of cigarette smoking with coronary thrombosis.⁶⁸ Cigarette smoking predicts a presentation of acute myocardial infarction versus unstable angina.^69–71 Among men with coronary disease who died suddenly, smoking was equally prevalent among those with vulnerable plaque rupture and with plaque erosion,⁶⁸ whereas in women who died of sudden coronary death, smoking appeared strongly associated with plaque erosion.⁷² Cigarette smoking may therefore be associated with fibrous plaque erosion more than with atheromatous plaque rupture.

	Smoking May Activate Vascular Sources of Matrix Metalloproteinases

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
Activated macrophages, mast cells, T lymphocytes, endothelial cells, and VSMCs are the principal sources of matrix metalloproteinases in the vasculature.⁷³ Cigarette smoke, by increasing vascular inflammation and vascular reactive oxygen species, has the potential to increase matrix metalloproteinase expression by each of these cell types.

Leukocytes
Mast cells participate actively in the inflammatory process of atherosclerotic plaques and perhaps specifically in plaque rupture.⁷⁴ Mast cell chymase and tryptase activate matrix metalloproteinases types 1 and 3, and activated mast cells also secrete matrix metalloproteinases types 1 and 9.⁷⁵ Mast cells are activated by oxidized LDL⁷⁶ and reactive oxygen species.⁷⁷ T lymphocytes in atherosclerotic plaques also express matrix metalloproteinases.⁵⁰ T lymphocytes are activated by oxidized LDL,⁷⁸ inflammatory cytokines,⁷⁹ and interaction with adhesion molecules.⁸⁰ The uptake of oxidized LDL induces activation of macrophages, leading to the release of matrix metalloproteinases.⁸¹ Monocyte adherence to endothelial cells increases MMP-9 activity.⁸²

VSMCs
VSMCs stimulated with IL-1 and tumor necrosis factor (TNF)- synthesize gelatinases, interstitial collagenase, and stromelysin.⁸³ Cigarette smoking is associated with increased circulating levels of TNF and IL-1ß as well as increased monocyte expression of IL-1ß.⁸⁴ Nicotine increases PDGF expression from platelets.⁸⁵ Nicotine and cotinine directly stimulate VSMC collagenase, stromelysin, and gelatinase expression.⁸⁶

Endothelial Cells
TNF- and IL-1 induce matrix metalloproteinase expression by endothelial cells.⁸⁷ Coculture of vascular endothelial cells with monocytes increases matrix metalloproteinase expression,⁸⁸ and cigarette smoke increases monocyte adhesion to endothelial cells.^31,89 Ligation of CD40 on endothelial cells is associated with increased metalloproteinase expression,⁹⁰ and cigarette smokers have upregulation of the CD40/CD40L dyad.⁹¹ These data suggest that cigarette smoke associated inflammation and oxidative stress may induce matrix metalloproteinase expression by key cellular sources of these enzymes.

	Smoking and Regulation of Matrix Metalloproteinase Activity

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
Activity of matrix metalloproteinases is regulated at the levels of gene transcription, proenzyme activation, and endogenous inhibitors of matrix metalloproteinases (Figure).³ Cigarette smoke-induced inflammation and oxidative stress have the potential to induce and inhibit matrix metalloproteinase activity at multiple levels. Reactive oxygen species⁹² and decreased nitric oxide activity⁹³ induce matrix metalloproteinase transcription. Cigarette smoke may increase matrix metalloproteinase expression via activation of inflammatory transcription factors. The expression of the AP-1 transcription factor complex is positively associated with matrix metalloproteinase expression,^94,95 and cigarette smoke is associated with increased expression of AP-1.^96,97 Secretion of MMP-1 and MMP-3 from macrophages stimulated in vitro or in vivo depends on the activation of NF-B,⁹⁸ and NF-B is required for cytokine upregulation of MMP-1, MMP-3, and MMP-9 in VSMCs.⁹⁹ Cigarette smoke itself is associated with activation of NF-B.¹⁰⁰ Plasmin activates matrix metalloproteinases, and smoking is associated with increased plasminogen activator levels.¹⁰¹ Reactive oxygen species activate latent proforms of matrix metalloproteinases,¹⁰² and antioxidant species decrease matrix metalloproteinase expression and activation.⁹² Nitric oxide inhibits matrix metalloproteinase activation.¹⁰³ IL-1ß decreases tissue inhibitor of metalloproteinase expression.¹⁰⁴ Reactive oxygen species induce tissue inhibitor of metalloproteinase activity.¹⁰⁵ Smoking is associated with increased TGF-ß levels,¹⁰⁶ by which smoking may inhibit metalloproteinase gene expression³ and induce tissue inhibitor of metalloproteinase expression.¹⁰⁵ The effect of cigarette smoking on matrix metalloproteinase activity is therefore complex and would be determined by the balance of matrix metalloproteinase and tissue inhibitor of metalloproteinase activities.

View larger version (41K): [in this window] [in a new window]   Potential means by which cigarette smoke may increase matrix metalloproteinase (MMP) activity. Cigarette smoke-induced inflammation and oxidative stress has the potential to induce metalloproteinase gene expression, induce pro-enzyme activation, and inhibit endogenous inhibitors of metalloproteinase activity. Reactive oxygen species induce gene expression, activate latent pro-enzymes, and inhibit tissue inhibitors of metalloproteinases (TIMPs). Scavenging of nitric oxide can increase metalloproteinase gene expression and pro-enzyme activation. Inflammatory cytokines induce metalloproteinase gene expression. Not shown, increased TGF-ß levels associated with smoking may inhibit metalloproteinase gene expression and induce TIMPs. The effect of cigarette smoking on MMP activity is therefore complex and would be determined by the balance of MMP and TIMP activities.

Studies directly examining the effect of smoking on matrix metalloproteinase activity are sparse. Exposure of endothelial cells to cigarette smoke condensate induces expression of MMP-1, MMP-8, and MMP-9.¹⁰⁷ Carotid endarterectomy specimens from cigarette smokers have higher MMP-12 and lower TIMP-1 expression than those from nonsmokers, and this is associated with decreased elastin content.¹⁰⁸ Variation in the stromeolysin-1 gene and smoking status demonstrated synergy in conferring risk for myocardial infarction.¹⁰⁹

	Conclusion

Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
Whereas an extensive body of literature indirectly implicates matrix metalloproteinases in the pathogenesis of smoking-associated vascular disease, few studies directly addressing this question have been performed. Investigations into smoking-related lung disease provide a paradigm by which to explore the role of matrix metalloproteinases in smoking-related vascular disease. For example, these studies raise the question of cadmium in cigarette smoke as a potential mediator of disease. Another interesting question that remains to be answered is whether the stronger association of smoking with peripheral than coronary atherosclerotic disease might be explained by spatial differences in MMP expression or activation. More clearly defining the role of matrix metalloproteinases in smoking related-vascular disease may provide new opportunities for the treatment of vascular disease among smokers.

Received September 20, 2005; accepted November 28, 2005.

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Top Abstract Introduction Epidemiology of Smoking... Smoking-Related Vascular... Matrix Metalloproteinases Matrix Metalloproteinases and... Smoking, Matrix... Epidemiology of Smoking... Smoking May Activate Vascular... Smoking and Regulation of... Conclusion References

 
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