Matrix metalloproteinase inhibitor properties of tetracyclines: Therapeutic potential in cardiovascular diseases

doi:10.1016/j.phrs.2011.05.005

Pharmacological Research

Volume 64, Issue 6, December 2011, Pages 551-560

https://doi.org/10.1016/j.phrs.2011.05.005 Get rights and content

Abstract

Matrix metalloproteinases (MMPs) are a family of proteases best known for their capacity to proteolyse several proteins of the extracellular matrix. Their increased activity contributes to the pathogenesis of several cardiovascular diseases. MMP-2 in particular is now considered to be also an important intracellular protease which has the ability to proteolyse specific intracellular proteins in cardiac muscle cells and thus reduce contractile function. Accordingly, inhibition of MMPs is a growing therapeutic aim in the treatment or prevention of various cardiovascular diseases. Tetracyclines, especially doxycycline, have been frequently used as important MMP inhibitors since they inhibit MMP activity independently of their antimicrobial properties. In this review we will focus on the intracellular actions of MMPs in some cardiovascular diseases including ischemia and reperfusion (I/R) injury, inflammatory heart diseases and septic shock; and explain how tetracyclines, as MMP inhibitors, have therapeutic actions to treat such diseases. We will also briefly discuss how MMPs can be intracellularly regulated and activated by oxidative stress, thus cleaving several important proteins inside cells. In addition to their potential therapeutic effects, MMP inhibitors may also be useful tools to understand the biological consequences of MMP activity and its respective extra- and intracellular effects.

Introduction

Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, first discovered in 1962 by Gross and Lapiere, as a collagen-degrading enzyme activity responsible for tadpole tail morphogenesis [1]. Since then, especially due to their ability to degrade several proteins of the extracellular matrix, MMPs have been an important subject of study in normal physiological processes, such as angiogenesis and embryogenesis [2], [3], as well as in diverse diseases such as arthritis, cancer and aortic aneurysm [4], [5], [6].

MMPs are referred to numerically from 1 through 28. They have been traditionally grouped according to their extracellular matrix substrates, primary structure or subcellular localization as: gelatinases (MMP-2 and -9), collagenases (MMP-1, -8, and -13), stromelysins (MMP-3 and -10), matrilysins (MMP-7 and MMP-26), metalloelastases (MMP-12) and membrane-type MMPs (MMP-14–16 and MMP-23–25) [7]. Of this varied family, MMP-2 and -9 are seen as significant contributors in several cardiovascular diseases, including atherosclerosis, hypertension, heart failure and ischemic heart diseases [8], [9], [10], [11], [12], [13]. Besides their well known action in extracellular matrix remodeling, studies have shown that MMP-2 in particular also plays important intracellular roles [14]. MMP-2 is activated inside cardiac myocytes in injuries associated with increased oxidative stress including I/R [13] or exposure to pro-inflammatory cytokines, thus cleaving susceptible intracellular proteins that are essential for the ability of the cell regulate contraction, such as troponin I [15], [16], myosin-light chain-1 [17], α-actinin [18] and titin [19].

In the heart, MMP-2 is ubiquitously expressed in normal cardiac myocytes and fibroblasts [20], which implies a yet undefined role in normal heart physiology, and underlies several reports of its involvement in cardiac pathologies. Likewise, MMP-2 is found to be constitutively expressed in vascular smooth muscle cells and endothelium of both arteries and normal veins [21], [22]. MMP-9 is normally associated with activated inflammatory cells such as leukocytes and macrophages [23] and is not present in cardiac myocytes aortae or vena cava from healthy humans and rats, although its protein levels in rat aortae are increased in cardiovascular diseases such as hypertension [24].

Because MMPs are involved in some cardiovascular diseases, their inhibition may be an attractive therapeutic aim in the treatment or prevention of such diseases. In this review we will focus on the acute intracellular actions of MMP-2 in some cardiovascular diseases including I/R injury, inflammatory heart diseases and septic shock, and clarify how MMP inhibitors including tetracyclines have therapeutic actions to treat such diseases.

Section snippets

MMP structure, activation and regulation

MMPs are initially synthesized as zymogens or ‘pro-MMPs’, with an autoinhibitory hydrophobic propeptide that shields an essential Zn²⁺ ion present in the catalytic domain [25]. The propeptide has the highly conserved PRCGVPD sequence which helps in the binding of the cysteine thiol to Zn²⁺ in the catalytic site, preventing its interaction with substrates. Several MMPs also have a flexible hinge region with a haemopexin-binding domain linked to their C-terminal end. The hinge region and

Pharmacological inhibitors of MMPs: focus on the tetracyclines

Pharmacological inhibition of MMPs relies on the ability of drugs to chelate the Zn²⁺ ion. So far, MMP inhibitors such as batimastat, marimastat, GM-6001 (ilomastat or gelardin), PD-166793 [57] and ONO-4817 [58] have been used as very powerful tools in experimental models of disease. However, their Zn²⁺ chelating property makes them nonselective inhibitors amongst the MMPs, since the Zn²⁺ ion is present in the active and other sites in the catalytic domain of all MMPs. An attempt to develop

Physiological role of MMPs in the development of heart and vasculature

Largely due to their ability to degrade several extracellular matrix proteins, MMPs are important in embryonic heart development [3] and in adaptive vascular remodeling [78] during exercise and pregnancy. They are key players in angiogenesis [2], [79], heart valve development and especially heart tube formation [80]. Inhibition of MMP-2 in chick embryos with ilomastat or MMP-2 neutralizing antibody caused significant cardiac tube defects, cardia bifida and disruption in the looping direction

Discovery of intracellular MMP activity in myocardial I/R injury

There are several mechanisms which mediate myocardial I/R injury and many are a result of enhanced oxidative stress within heart muscle. These include an imbalance in energy substrate preference for ATP production and a defect in Na/H⁺ and Na⁺/Ca²⁺ transporters [85]. In addition, some mechanisms responsible for the sarcoplasmic reticulum Ca²⁺ uptake are impaired, thus resulting in intracellular Ca²⁺ accumulation and activation of some Ca²⁺-dependent proteases [86], [87].

MMP-2 specifically has

MMP inhibition in inflammatory heart diseases

Elevated MMP activity has been linked to structural changes and impaired mechanical function associated with cardiovascular inflammatory disorders such as Kawasaki disease, viral myocarditis, Chagasic cardiomyopathy and sepsis [106], [107], [108]. Kawasaki disease is an acute inflammatory syndrome which involves systemic vascular inflammation and is accompanied by coronary artery dilatation and aneurysm. High levels of MMP-2 were observed in coronary arteries [109] and high levels of MMP-9 and

MMPs in the regulation of vascular tone

Several studies suggested that altered levels and activity of MMPs may be implicated in vascular dysfunction and tissue remodeling of many cardiovascular diseases, such as atherosclerosis, aneurysm and hypertension [8], [117]. Because of their ability to proteolyze a variety of extracellular matrix proteins, increased MMP activity promotes degradation of the extracellular matrix, the migration and proliferation of vascular smooth muscle cells and monocyte invasion into the intima [8], [118],

MMP inhibition in sepsis: focus on vascular effects

Sepsis or septic shock, a systemic bacterial infection which stimulates an excessive and harmful inflammatory response, is one of the most frequent causes of mortality in the world [139], [140]. Its cardiovascular manifestations include intense myocardial dysfunction and severe arterial hypotension [139], [141], caused in part by vascular hyporeactivity to some vasoconstrictor agonists. This hyporeactivity is a severe problem for treating sepsis since high doses of vasoconstrictors are

Conclusions

First thought to only degrade proteins of the extracellular matrix and contribute to maladaptive cardiovascular remodeling, MMP-2 is now considered to be an important intracellular protease, which is able to also proteolysis several intracellular proteins and reduce contractile function both in cardiac and smooth muscle cells. The ability of tetracyclines to inhibit MMP activity and thereby effectively treat a gamut of cardiovascular diseases outlined here should be carefully exploited and

Acknowledgements

We thank Dawne Colwell for help with the illustrations and Lorne Golub for his helpful comments on the manuscript. Studies in the Schulz laboratory reported here have been generously supported by the Canadian Institutes of Health Research (CIHR), the Heart and Stroke Foundation of Alberta, NWT & Nunavut and the Alberta Heritage Foundation for Medical Research (AHFMR). RS was an AHFMR scientist. MMC and ADK are fellows of the Heart and Stroke Foundation of Canada. NY receives studentship support

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Many commonly prescribed medications exhibit pleotropic effects, demonstrating potential clinical benefits beyond their normal therapeutic uses. Two commonly prescribed medications, which exhibit potential pleotropic actions in the treatment of CVD are methotrexate (MTX) and doxycycline (DOX) (Bench, Jeremias, & Brown, 2011; Castro, Kandasamy, Youssef, & Schulz, 2011; Micha et al., 2011; Reiss et al., 2008). The question arises how two medications with such disparate clinical uses: MTX originally developed as a chemotherapeutic agent and DOX an antibiotic, would demonstrate benefit in the treatment of CVD.
Many medications exhibit clinical benefits that are unrelated to their primary therapeutic uses. In many cases, the mechanisms underpinning these pleotropic effects are unknown. Two commonly prescribed medications that exhibit pleotropic benefits in cardiovascular disease and other diseases associated with chronic inflammation are methotrexate (MTX) and doxycycline (DOX). The vast majority of cardiovascular disease is associated with atherosclerosis. Because atherosclerosis is a chronic inflammatory disease, possible mechanisms by which MTX and DOX reduce inflammation have been investigated. Interestingly, the primary structure of both of these medications contain aromatic phenolic rings, which resemble polyphenols that are known to possess antioxidant activity. Inflammation and oxidative stress are intimately related. Inflammation promotes oxidative stress, which in turn leads to further inflammation; in this way, oxidative stress and inflammation can establish a self-perpetuating cycle. It has been shown that MTX and DOX act as antioxidants and are capable of scavenging free radicals and the reactive oxygen species (ROS) superoxide (O₂⁻). Furthermore, both MTX and DOX inhibit the formation of malondialdehyde acetaldehyde (MAA) adducts, products of oxidative stress and lipid peroxidation. Importantly, MAA-adducts are highly immunogenic and initiate inflammatory responses; thereby, fueling the cycle of inflammation and oxidative stress that results in chronic inflammation. Thus, reducing the formation of MAA-adducts may ameliorate inflammation that leads to ROS production and in this way, break the self-sustaining cycle of oxidative stress and inflammation. It is possible that the under-recognized antioxidant properties of these medications may be a mechanism by which they and other medications provide pleotropic benefit in the treatment of chronic inflammatory disease.
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ReviewMatrix metalloproteinase inhibitor properties of tetracyclines: Therapeutic potential in cardiovascular diseases

Abstract

Introduction

Section snippets

MMP structure, activation and regulation

Pharmacological inhibitors of MMPs: focus on the tetracyclines

Physiological role of MMPs in the development of heart and vasculature

Discovery of intracellular MMP activity in myocardial I/R injury

MMP inhibition in inflammatory heart diseases

MMPs in the regulation of vascular tone

MMP inhibition in sepsis: focus on vascular effects

Conclusions

Acknowledgements

Exp Cell Res

Atherosclerosis

J Mol Cell Cardiol

Matrix Biol

J Biol Chem

J Biol Chem

Arch Biochem Biophys

Biochem Pharmacol

FEBS Letters

J Biol Chem.

Biochem Biophys Res Commun

J Biol Chem

J Biol Chem

FEBS Lett

J Biol Chem

Lancet Neurol.

J Surg Res

J Surg Res

Int J Cardiol

Pharmacol Res

J Mol Cell Cardiol

FEBS Lett

Curr Opin Pharmacol

Pharmacol Rep

FEBS Lett

FEBS Lett

J Thorac Cardiovasc Surg

Collagenolytic activity in amphibian tissues: a tissue culture assay

Proc Natl Acad Sci USA

Matrix metalloproteinases: effectors of development and normal physiology

Genes Dev

Metalloproteinases, inflammation, and rheumatoid arthritis

Ann Rheum Dis

Matrix metalloproteinases and tumor metastasis

Cancer Metast Rev

Matrix metalloproteinase-2: the forgotten enzyme in aneurysm pathogenesis

Ann N Y Acad Sci

Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry

Circ Res

Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly

Circ Res

Matrix metalloproteinase inhibition after myocardial infarction: a new approach to prevent heart failure?

Circ Res

Matrix metalloproteinases and cardiovascular disease

Circ Res

Myocardial matrix degradation and metalloproteinase activation in the failing heart: a potential therapeutic target

Cardiovasc Res

Matrix metalloproteinase-2 contributes to ischemia-reperfusion injury in the heart

Circulation

Intracellular targets of matrix metalloproteinase-2 in cardiac disease: rationale and therapeutic approaches

Annu Rev Pharmacol Toxicol

Intracellular action of matrix metalloproteinase-2 accounts for acute myocardial ischemia and reperfusion injury

Circulation

Matrix metalloproteinase-2 mediates cytokine-induced myocardial contractile dysfunction

Cardiovasc Res

Degradation of myosin light chain in isolated rat hearts subjected to ischemia-reperfusion injury: a new intracellular target for matrix metalloproteinase-2

Circulation

Titin is a target of MMP-2: implications in myocardial ischemia/reperfusion injury

Circulation

Matrix metalloproteinase synthesis and expression in isolated LV myocyte preparations

Am J Physiol

Increased expression of matrix metalloproteinases and matrix degrading activity in vulnerable regions of human atherosclerotic plaques

J Clin Invest

Regulation of matrix metalloproteinase expression in human vein and microvascular endothelial cells, Effects of tumour necrosis factor alpha, interleukin 1 and phorbol ester

Biochem J

Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure

Nat Med

Review
Matrix metalloproteinase inhibitor properties of tetracyclines: Therapeutic potential in cardiovascular diseases