Matrix metalloproteinases in atherosclerosis: role of nitric oxide, hydrogen sulfide, homocysteine, and polymorphisms

Abstract

Atherosclerosis is an inflammatory process that involves activation of matrix metalloproteinases (MMPs); MMPs degrade collagen and allow for smooth-muscle cell migration within a vessel. Moreover, this begets an accumulation of other cellular material, resulting in occlusion of the vessel and ischemic events to tissues in need of nutrients. Homocysteine has been shown to activate MMPs via an increase in oxidative stress and acting as a signaling molecule on receptors like the peroxisome proliferator activated receptor-γ and N-methyl-D-aspartate receptor. Nitric oxide has been shown to be beneficial in some cases of deactivating MMPs. However, in other cases, it has been shown to be harmful. Further studies are warranted on the scenarios that are beneficial versus destructive. Hydrogen sulfide (H2S) has been shown to decrease MMP activities in all cases in the literature by acting as an antioxidant and vasodilator. Various MMP-knockout and gene-silencing models have been used to determine the function of the many different MMPs. This has allowed us to discern the role that each MMP has in promoting or alleviating pathological conditions. Furthermore, there has been some study into the MMP polymorphisms that exist in the population. The purpose of this review is to examine the role of MMPs and their polymorphisms on the development of atherosclerosis, with emphasis placed on pathways that involve nitric oxide, hydrogen sulfide, and homocysteine.

Keywords: bone remodeling; collagen cross-linking; homocysteine; hydrogen sulfide; matrix metalloproteinases; nitric oxide; oxidative stress.

Figure 1

MMPs and smooth-muscle cell proliferation. Notes: MMP-1, -2, -3, -8, and -9 have been shown to be involved in facilitating vascular remodeling by degrading the matrix separating the intima from the media and allowing smooth-muscle cell migration from the media to the intima. This smooth-muscle cell migration results in the occlusion of vessel walls and decreased blood flow to tissues in need of oxygen and nutrients carried by the blood. Abbreviation: MMP, matrix metalloproteinase.

Figure 2

MMP-10 as clot destroyer in atherosclerosis. Notes: LDL molecules and monocytes, including macrophages and T-cells, transcend the endothelial layer of the intima of blood vessels via transporters like VCAM-1. Macrophages within the intima will engulf oxidized LDL molecules and form foam cells. T-cells will release inflammatory cytokines, such as TNFα and IFNγ, that recruit molecules further into the intima. Smooth-muscle cells also proliferate into the intima layer from the media layer, which results in further occlusion of vessels. MMP-10 attacks the fibrinogen molecule and prevents its conversion to fibrin, which allows for the netting of platelets and resultant plaque occlusion. Abbreviations: IFN, Interferon; LDL, low-density lipoprotein; M, macrophage; MMP, matrix metalloproteinase; T, T lymphocyte; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule.

Figure 3

Mechanism of vasodilation. Notes: H₂S can be acquired via various conversion steps of Hcy in an anaerobic pathway. Hcy is converted to cystathionine by CBS and then to L-cysteine by the CSE enzyme. L-Cysteine can be converted to H₂S, which is used by adenylyl cyclase to convert ATP to cAMP involved in vasorelaxation. The substrates oxygen and L-arginine are known to be used by eNOS, nNOS, and iNOS enzymes to produce nitric oxide, which potentiates guanylyl cyclase to convert GTP to cGMP. cGMP is a molecule that allows for vascular relaxation. PDE5 inhibits vasorelaxation, as its activation converts cGMP to GMP and potentiates vasoconstriction. Abbreviations: Hcy, homocysteine; CBS, cystathionine β-synthase; CSE, cystathionine γ-lyase; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; eNOS, endothelial nitric oxide synthetase; nNOS, neuronal NOS; iNOS, inducible NOS; GTP, guanosine triphosphate; cGMP, cyclic guanosine monophosphate; PDE, phosphodiesterase; ADMA, asymmetric dimethylarginine; DDAH, dimethylarginine dimethylaminohydrolase; MST, 3-mercaptopyruvate sulfurtransferase; GC, guanylyl cyclase; AC, adenylyl cyclase.