Absence of SPARC results in increased cardiac rupture and dysfunction after acute myocardial infarction

The matricellular protein SPARC (secreted protein, acidic and rich in cysteine, also known as osteonectin) mediates cell–matrix interactions during wound healing and regulates the production and/or assembly of the extracellular matrix (ECM). This study investigated whether SPARC functions in infarct healing and ECM maturation after myocardial infarction (MI). In comparison with wild-type (WT) mice, animals with a targeted inactivation of SPARC exhibited a fourfold increase in mortality that resulted from an increased incidence of cardiac rupture and failure after MI. SPARC-null infarcts had a disorganized granulation tissue and immature collagenous ECM. In contrast, adenoviral overexpression of SPARC in WT mice improved the collagen maturation and prevented cardiac dilatation and dysfunction after MI. In cardiac fibroblasts in vitro, reduction of SPARC by short hairpin RNA attenuated transforming growth factor β (TGF)–mediated increase of Smad2 phosphorylation, whereas addition of recombinant SPARC increased Smad2 phosphorylation concordant with increased Smad2 phosphorylation in SPARC-treated mice. Importantly, infusion of TGF-β rescued cardiac rupture in SPARC-null mice but did not significantly alter infarct healing in WT mice. These findings indicate that local production of SPARC is essential for maintenance of the integrity of cardiac ECM after MI. The protective effects of SPARC emphasize the potential therapeutic applications of this protein to prevent cardiac dilatation and dysfunction after MI

Thrombospondins in the heart: potential functions in cardiac remodeling

Cardiac remodeling after myocardial injury involves inflammation, angiogenesis, left ventricular hypertrophy and matrix remodeling. Thrombospondins (TSPs) belong to the group of matricellular proteins, which are non-structural extracellular matrix proteins that modulate cell–matrix interactions and cell function in injured tissues or tumors. They interact with different matrix and membrane-bound proteins due to their diverse functional domains. That the expression of TSPs strongly increases during cardiac stress or injury indicates an important role for them during cardiac remodeling. Recently, the protective properties of TSP expression against heart failure have been acknowledged. The current review will focus on the biological role of TSPs in the ischemic and hypertensive heart, and will describe the functional consequences of TSP polymorphisms in cardiac disease

Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: a temporal and spatial window

The post-myocardial infarction wound repair process involves temporarily overlapping phases that include inflammation, formation of granulation tissue, scar formation, and overall left ventricle (LV) remodelling. The myocardial extracellular matrix (ECM) plays an important role in maintaining the structural and functional integrity of the heart and is centrally involved in wound repair post-myocardial infarction (MI). The main proteolytic system involved in the degradation of the ECM in the heart is the matrix metalloproteinase (MMPs) system. The present review will focus on the importance of the unique temporal and spatial window of MMPs and their inhibitors (TIMPs) within the different wound healing phases post-MI. It summarizes (1) the MMP/TIMP levels at different time points post-MI, (2) the alterations seen in post-MI healing in genetically modified mice, and (3) the effects and limitations of therapeutic MMP-inhibition post-M

Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: a temporal and spatial window

The post-myocardial infarction wound repair process involves temporarily overlapping phases that include inflammation, formation of granulation tissue, scar formation, and overall left ventricle (LV) remodelling. The myocardial extracellular matrix (ECM) plays an important role in maintaining the structural and functional integrity of the heart and is centrally involved in wound repair post-myocardial infarction (MI). The main proteolytic system involved in the degradation of the ECM in the heart is the matrix metalloproteinase (MMPs) system. The present review will focus on the importance of the unique temporal and spatial window of MMPs and their inhibitors (TIMPs) within the different wound healing phases post-MI. It summarizes (1) the MMP/TIMP levels at different time points post-MI, (2) the alterations seen in post-MI healing in genetically modified mice, and (3) the effects and limitations of therapeutic MMP-inhibition post-MI.status: publishe

Matricellular proteins in the heart: possible role during stress and remodeling

Matricellular proteins are extracellular matrix proteins that modulate cell-matrix interactions and cell function, and do not seem to have a direct structural role. The family includes tenascin-C (TN-C), tenascin-X (TN-X), osteonectin, osteopontin, thrombospondin-1 (TSP1) and thrombospondin-2 (TSP2). Expression of matricellular proteins is high during embryogenesis, but almost absent during normal postnatal life. Interestingly, it re-appears in response to injury. Left ventricular remodeling is a complicated process that occurs in the stressed heart, and is still not completely understood. Several members of the matricellular protein family, like tenascin-C, osteopontin, and osteonectin are up-regulated after cardiac injury. Therefore, this group of proteins may have crucial functions in the heart coping with stress. This review will focus on the expression, regulation and function of these matricellular proteins, and will discuss the crucial functions that these proteins might exert during remodeling of the stressed hear

Atlas der Alpenflora / Mannsschildartiger Steinbrech

Magasság: 1800-3200 M.Előfordulási hely: Alpenkette, feuchte StellenVirágzás: Juni, Jul

Syndecan-1 Amplifies Angiotensin II–Induced Cardiac Fibrosis

Syndecan-1 (Synd1) is a transmembrane heparan sulfate proteoglycan that functions as a coreceptor for various growth factors and modulates signal transduction. The present study investigated whether Synd1, by affecting growth factor signaling, may play a role in hypertension-induced cardiac fibrosis and dysfunction. Expression of Synd1 was increased significantly in mouse hearts with angiotensin II–induced hypertension, which was spatially related to cardiac fibrosis. Angiotensin II significantly impaired fractional shortening and induced cardiac fibrosis in wild-type mice, whereas these effects were blunted in Synd1-null mice. Angiotensin II significantly increased cardiac expression of connective tissue growth factor and collagen type I and III in wild-type mice, which was blunted in Synd1-null mice. These findings were confirmed in vitro, where angiotensin II induced the expression of both connective tissue growth factor and collagen I in fibroblasts. The absence of Synd1 in either Synd1-null fibroblasts, after knockdown of Synd1 by short hairpin RNA, or after inhibition of heparan sulfates by protamine attenuated this increase, which was associated with reduced phosphorylation of Smad2. In conclusion, loss of Synd1 reduces cardiac fibrosis and dysfunction during angiotensin II–induced hypertension.status: publishe