Translational perspectives on matrix metalloproteinase 8 and other inflammatory biomarkers in cardiovascular diseases

Abstract Cardiovascular diseases (CVD), and especially atherosclerotic vascular diseases (ASVD), are the largest cause of morbidity and premature death worldwide. Coronary heart disease (CHD) and cerebrovascular disease (stroke) are common and severe manifestations of ASVD. Atherosclerosis is a chronic inflammatory disease and lipoprotein metabolism disorder. If the regulation of inflammatory process is disturbed, the systemic release of pro-inflammatory mediators, including matrix metalloproteinases (MMPs), may lead to a low-grade systemic inflammation, which is a risk factor for CVDs. MMPs are enzymes that are responsible for the degradation of the extracellular matrix (ECM) during growth and tissue renewal but also in many pathological conditions. These ECM degrading proteases and their regulators play an important role in atherogenesis and subsequent plaque rupture, leading to acute cardiovascular manifestations. The pivotal role of MMPs in atherosclerosis has raised interest in the development of drug therapies targeting these proteases. Doxycycline has inhibitory effects on some MMPs in addition to its antimicrobial properties. The main objective of this thesis project was to investigate the potential of these inflammatory mediators as biomarkers, risk factors, and therapeutic targets in CVD. The special focus was on MMP-8 and its main regulator, tissue inhibitor of matrix metalloproteinase (TIMP)-1. The results of this study show that a high serum MMP-8 concentration indicates an acute cardiac condition and predicts a future CVD event. In addition to MMP-8, MMP-7 is a potential biomarker for incident CVD. The balance between these MMPs and their tissue inhibitor may indicate vulnerability to plaque rupture. Measurement of serum MMP-8 concentration is reliable, anti-invasive and inexpensive and can be done in hospital settings. We also show that regular-dose doxycycline decreases the systemic inflammatory burden in patients with earlier myocardial infarction and is a promising anti-inflammatory therapy in the prevention of CVDs with relatively minor side effects. In conclusion, MMP-8 and TIMP-1 can be considered inflammatory risk markers of CVD events and death, and they can be utilized both for diagnostic and screening purposes. The inhibition of MMP-8 by doxycycline may reduce the systemic inflammatory burden in patients with myocardial infarction.Tiivistelmä Sydän- ja verisuonisairaudet, erityisesti ateroskleroottiset valtimosairaudet, ovat maailman yleisin sairastuvuuden ja ennenaikaisen kuoleman syy. Sepelvaltimotauti ja aivohaveri ovat ateroskleroottisen valtimosairauden yleisiä ja vakavia ilmenemismuotoja. Ateroskleroosi on krooninen tulehduksellinen sairaus ja lipoproteiiniaineenvaihdunnan häiriö. Jos tulehdustapahtuma häiriintyy, elimistöön vapautuvat tulehdusvälittäjäaineet, kuten matriksin metalloproteinaasit (MMP), voivat aiheuttaa elimistön matala-asteisen tulehduksen, joka on sydän- ja verisuonisairauksien riskitekijä. MMP:t ovat entsyymejä, jotka pilkkovat solunväliainetta kasvun ja kudosten uusiutumisen mutta myös monien tautitilojen yhteydessä. Nämä soluväliainetta hajottavat proteaasit ja niiden säätelijät ovat tärkeässä roolissa ateroskleroottisen plakin muodostumisessa ja repeämisessä, joka johtaa äkillisiin sydäntautitapahtumiin. Matriksin metalloproteinaasien keskeinen rooli ateroskleroosissa on herättänyt kiinnostusta niihin kohdistuvan lääkehoidon kehittämiseen. Doksisykliinillä on joidenkin MMP-entsyymien toimintaa estävä vaikutus antimikrobiaalisten ominaisuuksiensa lisäksi. Tämän väitöskirjatutkimuksen päätavoitteena oli tutkia näiden tulehdusvälittäjäaineiden mahdollisuuksia biomarkkereina, riskitekijöinä ja lääkehoidon kohteena sydän- ja verisuonisairauksissa. Erityinen kiinnostuksen kohde oli MMP-8 ja sen pääsäätelijä ja kudosestäjä, tissue inhibitor of matrix metalloproteinase (TIMP)-1. Tämän tutkimuksen tulokset osoittavat, että seerumin korkea MMP 8 pitoisuus viittaa akuuttiin sydäntautiin ja ennakoi tulevaa sydäntautitapahtumaa. MMP-8:n lisäksi MMP-7 on lupaava sydäntapahtuman biomarkkeri. Näiden matriksin metalloproteinaasien ja niiden kudossäätelijä TIMP-1:n välinen tasapaino voi liittyä ateroskleroottisen plakin haurauteen. Seerumin MMP-8:n mittaus on luotettavaa, kajoamatonta ja edullista, ja mahdollista toteuttaa myös sairaalaolosuhteissa. Näytämme myös, että doksisykliini vähentää elimistön tulehdustaakkaa sydäninfarktin sairastaneilla potilailla ja että se on sydäntautien ehkäisyssä lupaava anti-inflammatorinen lääke, jolla on suhteellisen vähän sivuvaikutuksia. Johtopäätöksenä on, että MMP-8:aa ja TIMP-1:tä voidaan pitää lupaavina sydän- ja verisuonitautien sekä kuoleman biomarkkereina sekä diagnostiikka- että seulontakäytössä. Lisäksi tutkimustulokset osoittavat, että MMP-8:n esto doksisykliinillä voi vähentää elimistön tulehdustaakkaa sydänkohtauksen sairastaneilla potilailla

Periodontal health and serum, saliva matrix metalloproteinases in patients with mild chronic obstructive pulmonary disease

WOS: 000318187400001PubMed ID: 22967248YildirimE, Kormi I, Basoglu OK, Gurgun A, Kaval B, Sorsa T, Buduneli N. Periodontal health and serum, saliva matrix metalloproteinases in patients with mild chronic obstructive pulmonary disease. J Periodont Res 2013; 48: 269-275. (C) 2012 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Background and Objectives The present casecontrol study aimed to evaluate comparatively the salivary and serum levels of matrix metalloproteinases (MMP)-8 and- 13 and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in patients with mild chronic obstructive pulmonary disease (COPD) and non-COPD controls. Material and Methods Clinical periodontal measurements were recorded before any periodontal intervention in 36 patients with mild COPD and 20 non-COPD controls admitted to Ege University Department of Chest Diseases COPD outpatient clinic (zmir, Turkey). Salivary and serum levels of MMP-8, MMP-13, and TIMP-1 were determined by immunofluorometric assay (IFMA) and enzyme-linked immunosorbent assay (ELISA). Data were analyzed with non-parametric statistical tests. Results Patients with COPD were significantly older than the control group (p0.05). Salivary MMP-8, MMP-13, and TIMP-1 levels were similar in both groups (p>0.05). Conclusions The present findings suggest that immunodetection of MMP-8 is dependent on the selected techniques and even with mild COPD some systemic inflammatory markers such as MMP-8 tend to increase. However, the present clinical periodontal and biochemical findings do not provide support for the previously proposed interaction between COPD and periodontal diseases

Age-related wayfinding differences in real large-scale environments: detrimental motor control effects during spatial learning are mediated by executive decline?

The aim of this study was to evaluate motor control activity (active vs. passive condition) with regards to wayfinding and spatial learning difficulties in large-scale spaces for older adults. We compared virtual reality (VR)-based wayfinding and spatial memory (survey and route knowledge) performances between 30 younger and 30 older adults. A significant effect of age was obtained on the wayfinding performances but not on the spatial memory performances. Specifically, the active condition deteriorated the survey measure in all of the participants and increased the age-related differences in the wayfinding performances. Importantly, the age-related differences in the wayfinding performances, after an active condition, were further mediated by the executive measures. All of the results relative to a detrimental effect of motor activity are discussed in terms of a dual task effect as well as executive decline associated with aging