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

In patients with pseudoxanthoma elasticum a thicker and more elastic carotid artery is associated with elastin fragmentation and proteoglycans accumulation

Skin biopsies in patients with pseudoxanthoma elasticum (PXE) show elastic fiber fragmentation and calcium and proteoglycans accumulation. Assuming such changes to be present in the artery wall as well, we studied the influence of such alterations on function and structure of the human common carotid artery (CCA). Indeed, elastin fragmentation and increased calcium and proteoglycans content were present in the arteries of the two PXE patients examined. Internal diameter, distension and intima-media thickness (IMT) in the CCA of PXE patients (n = 19) and controls (n = 39) were determined by ultrasound (US). Pulse pressure was assessed in the brachial artery. The distensibility and compliance coefficients as well as the Young's modulus were calculated. Diameter and pulse pressure were not significantly different in PXE patients and controls. The distensibility and compliance coefficients were significantly greater in older PXE patients than in older controls. The distensibility coefficient decreased with age in both PXE patients and in controls. Unlike in controls, the compliance coefficient did not decrease and the Young's modulus barely increased with age in PXE patients. IMT was significantly greater at both younger and older ages and the Young's modulus was significantly smaller at older ages in PXE patients than in controls. The carotid artery is thicker and more elastic in PXE patients than in control subjects; differences are most pronounced at older ages. These alterations might be explained by the elastin fragmentation and proteoglycans accumulation as observed in these patient

Dynamic contrast-enhanced MR imaging of carotid atherosclerotic plaque: model selection, reproducibility, and validation

To compare four known pharmacokinetic models for their ability to describe dynamic contrast material-enhanced magnetic resonance (MR) imaging of carotid atherosclerotic plaques, to determine reproducibility, and to validate the results with histologic findings. The study was approved by the institutional medical ethics committee. Written informed consent was obtained from all patients. Forty-five patients with 30%-99% carotid stenosis underwent dynamic contrast-enhanced MR imaging. Plaque enhancement was measured at 16 time points at approximately 25-second image intervals by using a gadolinium-based contrast material. Pharmacokinetic parameters (volume transfer constant, K(trans); extracellular extravascular volume fraction, v(e); and blood plasma fraction, v(p)) were determined by fitting a two-compartment model to plaque and blood gadolinium concentration curves. The relative fit errors and parameter uncertainties were determined to find the most suitable model. Sixteen patients underwent imaging twice to determine reproducibility. Carotid endarterectomy specimens from 16 patients who were scheduled for surgery were collected for histologic validation. Parameter uncertainties were compared with the Wilcoxon signed rank test. Reproducibility was assessed by using the coefficient of variation. Correlation with histologic findings was evaluated with the Pearson correlation coefficient. The mean relative fit uncertainty (±standard error) for K(trans) was 10% ± 1 with the Patlak model, which was significantly lower than that with the Tofts (20% ± 1), extended Tofts (33% ± 3), and extended graphical (29% ± 3) models (P < .001). The relative uncertainty for v(p) was 20% ± 2 with the Patlak model and was significantly higher with the extended Tofts (46% ± 9) and extended graphical (35% ± 5) models (P < .001). The reproducibility (coefficient of variation) for the Patlak model was 16% for K(trans) and 26% for v(p). Significant positive correlations were found between K(trans) and the endothelial microvessel content determined on histologic slices (Pearson ρ = 0.72, P = .005). The Patlak model is most suited for describing carotid plaque enhancement. Correlation with histologic findings validated K(trans) as an indicator of plaque microvasculature, and the reproducibility of K(trans) was goo

Thrombospondin-2 is essential for myocardial matrix integrity: increased expression identifies failure-prone cardiac hypertrophy

Cardiac hypertrophy can lead to heart failure (HF), but it is unpredictable which hypertrophied myocardium will progress to HF. We surmised that apart from hypertrophy-related genes, failure-related genes are expressed before the onset of failure, permitting molecular prediction of HF. Hearts from hypertensive homozygous renin-overexpressing (Ren-2) rats that had progressed to early HF were compared by microarray analysis to Ren-2 rats that had remained compensated. To identify which HF-related genes preceded failure, cardiac biopsy specimens were taken during compensated hypertrophy and we then monitored whether the rat progressed to HF or remained compensated. Among 48 genes overexpressed in failing hearts, we focused on thrombospondin-2 (TSP2). TSP2 was selectively overexpressed only in biopsy specimens from rats that later progressed to HF. Moreover, expression of TSP2 was increased in human hypertrophied hearts with decreased (0.19+/-0.01) versus normal ejection fraction (0.11+/-0.03 [arbitrary units]; P <0.05). Angiotensin II induced fatal cardiac rupture in 70% of TSP2 knockout mice, with cardiac failure in the surviving mice; this was not seen in wild-type mice. In TSP2 knockout mice, angiotensin II increased matrix metalloproteinase (MMP)-2 and MMP-9 activity by 120% and 390% compared with wild-type mice (P <0.05). In conclusion, we identify TSP2 as a crucial regulator of the integrity of the cardiac matrix that is necessary for the myocardium to cope with increased loading and that may function by its regulation of MMP activity. This suggests that expression of TSP2 marks an early-stage molecular program that is activated uniquely in hypertrophied hearts that are prone to fai