|Institution:||University of Oulu|
|Keywords:||atherosclerosis; biomarkers; cardiovascular disease risk factors; low-grade inflammation; ateroskleroosi; biomarkkerit; matala-asteinen tulehdus; sydn- ja verisuonisairauksien riskitekijt; MMP-8; TIMP-1|
|Full text PDF:||http://urn.fi/urn:isbn:9789526215297|
AbstractCardiovascular 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. TiivistelmSydn- ja verisuonisairaudet, erityisesti ateroskleroottiset valtimosairaudet, ovat maailman yleisin sairastuvuuden ja ennenaikaisen kuoleman syy. Sepelvaltimotauti ja aivohaveri ovat ateroskleroottisen valtimosairauden yleisi ja vakavia ilmenemismuotoja.Ateroskleroosi on krooninen tulehduksellinen sairaus ja lipoproteiiniaineenvaihdunnan hiri. Jos tulehdustapahtuma hiriintyy, elimistn vapautuvat tulehdusvlittjaineet, kuten matriksin metalloproteinaasit (MMP), voivat aiheuttaa elimistn matala-asteisen tulehduksen, joka on sydn- ja verisuonisairauksien riskitekij. MMP:t ovat entsyymej, jotka pilkkovat solunvliainetta kasvun jaAdvisors/Committee Members: Sorsa, T. (Timo), Pussinen, P. (Pirkko).