Matrix Metalloproteinase-9 Expression in Calcified Human Aortic Valves

Abstract

The hallmarks of calcific aortic valve disease (CAVD) are the significant quantitative and qualitative changes that occur in the extracellular matrix (ECM), which ultimately lead to increased leaflet stiffness and obstruction of left ventricular outflow. Mounting evidence suggests that ECM remodeling not only contribute to valve cell dysfunction but also alter certain cell signaling pathways responsible for the initiation and progression of the disease state. Matrix metalloproteinases (MMPs), collectively called matrixins, are a family of enzymes known to participate in numerous ECM remodeling events during embryonic development and in disease. The aim of the present study was to evaluate whether changes in MMP-9 expression might be involved in the pathophysiology of CAVD. For this purpose, we have analyzed a total of 19 pathologic valves from patients who underwent aortic valve replacement for calcific aortic stenosis. Microscopically, the cusp tissue showed diffuse fibrosis, neovascularization, and abnormal ECM remodeling with collagen disorganization and mineralization. Western blot and immunohistochemical analyses have been performed on both the areas overlying and remote from the mineral deposits. Protein expression data evidenced a significant upregulation of MMP-9 in the calcified lesion area. Consistent with these observations, immunohistochemistry demonstrated that MMP-9 protein was almost exclusively localized near or around the mineralized nodules, whereas was generally quite weak or absent in areas devoid of any calcification. Our data suggest that MMP-9 may play a key role in CAVD probably by promoting the fibrotic and procalcific remodeling of the ECM.

Postnatal and Adult Aortic Heart Valves Have Distinctive Transcriptional Profiles Associated With Valve Tissue Growth and Maintenance Respectively

“…As indicated by the GO term z-score in Figure 3A , the overall expression of ECM transcripts does not significantly increase or decrease with age, yet there are considerable differences in the specific ECM-related mRNAs that are expressed between the two time points ( Table 3 ). Matrix metalloproteinases, or Mmps, are known to be expressed in both healthy and diseased valves and are associated with physiological and pathological remodeling of the ECM respectively ( 29 – 31 ). Also known as stromelysin-1, Mmp3 targets degradation of proteoglycans, collagens, and elastins ( 32 ) and this Mmp family member has been described in cancer ( 33 , 34 ), but little is known about Mmp3 in mouse valves.…”

TLR4 Stimulation Promotes Human AVIC Fibrogenic Activity through Upregulation of Neurotrophin 3 Production

“…MMP-9 is involved in maintaining fibroblast viability and promoting the production of pro-inflammatory factors, including IL-1β, IL-6, IL-8, and TNF-α in fibroblasts [38]. In addition, MMP-9 overproduction in AVICs is believed to promote valvular ECM remodeling [39]. However, the relative activity of MMP is modulated by their specific inhibitors, the tissue inhibitors of MMPs (TIMPs).…”

Iekaisīgie un neiekaisīgie riska faktori iegūtas aortas vārstuļa stenozes gadījumā. Promocijas darbs

“…-9 piemīt afinitāte pret denaturēto fibrillāro kolagēnu, pamatā membrānas proteīniem. MMP-9 piemīt arī proteolītiskā aktivitāte pret elastīnu un proteoglikāniem(Perrotta et al, 2016).MMP-3 darbojas uz visiem bazālās membrānas proteīniem, elastīnu un proteoglikāniem. MMP-3 piemīt spēja inducēt citu MMP proteolītisko aktivāciju (Spinale, 2007)…”

“…Turpmākie pētījumi varētu parādīt, vai 1G>2G MMP-1 polimorfismu var izmantot, lai prognozētu aortas vārstuļa stenozes iespējamo attīstību (Solache-Berrocal et al, 2016).Pētot vārstuļus, kas iegūti operācijas laikā no pacientiem ar kalcificējošu aortas vārstuļa stenozi, atrada, ka MMP-9 gandrīz pilnībā bija lokalizēts kalcifikācijas rajonos vai ap tiem. Var domāt, ka MMP-9 var būt nozīmīga loma, veicinot ekstracelulārās telpas fibrotisku un uz kalcifikāciju vērstu remodelāciju(Perrotta et al, 2016).…”