Matrix metalloproteinases and tissue inhibitors of metalloproteinases in extracellular matrix remodeling during left ventricular diastolic dysfunction and heart failure with preserved ejection fraction: A systematic review and meta-analysis

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are pivotal regulators of extracellular matrix (ECM) composition and could, due to their dynamic activity, function as prognostic tools for fibrosis and cardiac function in left ventricular diastolic dysfunction (LVDD) and heart failure with preserved ejection fraction (HFpEF). We conducted a systematic review on experimental animal models of LVDD and HFpEF published in MEDLINE or Embase. Twenty-three studies were included with a total of 36 comparisons that reported established LVDD, quantification of cardiac fibrosis and cardiac MMP or TIMP expression or activity. LVDD/HFpEF models were divided based on underlying pathology: hemodynamic overload (17 comparisons), metabolic alteration (16 comparisons) or ageing (3 comparisons). Meta-analysis showed that echocardiographic parameters were not consistently altered in LVDD/HFpEF with invasive hemodynamic measurements better representing LVDD. Increased myocardial fibrotic area indicated comparable characteristics between hemodynamic and metabolic models. Regarding MMPs and TIMPs; MMP2 and MMP9 activity and protein and TIMP1 protein levels were mainly enhanced in hemodynamic models. In most cases only mRNA was assessed and there were no correlations between cardiac tissue and plasma levels. Female gender, a known risk factor for LVDD and HFpEF, was underrepresented. Novel studies should detail relevant model characteristics and focus on MMP and TIMP protein expression and activity to identify predictive circulating markers in cardiac ECM remodeling

Combining tissue repair and tissue engineering ; bioactivating implantable cell-free vascular scaffolds

Synthetic replacement grafts for heart valves and small-diameter blood vessels such as coronary arteries have the potential to circumvent many of the limitations of currently available autologous grafting materials. Cell-free material incorporating biologically active compounds may guide the formation of fully autologous new tissue in situ derived from host cells after implantation. Inspiration for such bioactive compounds and their dynamics can be found in in vivo repair processes. Molecules such as stromal cell-derived factor 1a (SDF1a) that can attract progenitor cells from the bloodstream and modulate immune responses may be able to improve neotissue development in cell-free vascular and valvular grafts. Advances in the development of fully synthetic molecules and scaffold materials allow the spatial and temporal control of biologically active factors, enabling tissue engineers to mimic complex cellular signalling. This review focuses on combining knowledge of the molecular dynamics of factors involved in in vivo damage repair with the possibilities offered by newly developed synthetic materials. This approach has lead to encouraging results in the field of in situ vascular tissue engineering, and can ultimately lead to the development of off-the-shelf available vascular and valvular replacement grafts. © 2014 BMJ Publishing Group Ltd & British Cardiovascular Society

Environmental Influences on Endothelial to Mesenchymal Transition in Developing Implanted Cardiovascular Tissue-Engineered Grafts

Therapeutic cell differentiatio

Galectin-2 Expression is Dependent on the rs7291467 Single Nucleotide Polymorphism and Inhibits Collateral Artery Growth

Vascular Surger

Activin A induces a non-fibrotic phenotype in smooth muscle cells in contrast to TGF-beta

AIMS: Activin A and transforming growth factor-β1 (TGF-β1) belong to the same family of growth and differentiation factors that modulate vascular lesion formation in distinct ways, which we wish to understand mechanistically. METHODS AND RESULTS: We investigated the expression of cell-surface receptors and activation of Smads in human vascular smooth muscle cells (SMCs) and demonstrated that activin receptor-like kinase-1 (ALK-1), ALK-4, ALK-5 and endoglin are expressed in human SMCs. As expected, TGF-β1 activates Smad1 and Smad2 in these cells. Interestingly, activin A also induces phosphorylation of both Smads, which has not been reported for Smad1 before. Transcriptome analyses of activin A and TGF-β1 treated SMCs with subsequent Gene-Set Enrichment Analyses revealed that many downstream gene networks are induced by both factors. However, the effect of activin A on expression kinetics of individual genes is less pronounced than for TGF-β1, which is explained by a more rapid dephosphorylation of Smads and p38-MAPK in response to activin A. Substantial differences in expression of fibronectin, alpha-V integrin and total extracellular collagen synthesis were observed. CONCLUSIONS: Genome-wide mRNA expression analyses clarify the distinct modulation of vascular lesion formation by activin A and TGF-β1, most significantly because activin A is non-fibroti