The angiotensin–calcineurin–NFAT pathway mediates stretch-induced up-regulation of matrix metalloproteinases-2/-9 in atrial myocytes

Abstract

Our results present new insights in molecular mechanisms of ECM remodeling activity of atrial myocytes exposed to static stretch. The AT1-Cn-NFAT pathway is a potential mediator of MMP activation.

Extracellular Matrix Molecules: Potential Targets in Pharmacotherapy

“…Inhibition of cyclooxygenase enzymes -1 and -2 (Gasparini et al, 2003) Modulation of the synthesis of fibronectin (Ernst et al, 1995), various types of collagen (Ernst et al, 1995;Liu et al, 2007), large chondroitin sulfate proteoglycans (Okada et al, 1994), and HA (Sussmann et al, 2004); suppression of MMP expression, synthesis, and activity (Sadowski and Steinmeyer, 2001;Pavlovic et al, 2006) Other immunosuppressive drugs Cyclosporine A Calcineurin inhibitor (Ho et al, 1996) Differential effect on collagen synthesis and fibrosis (Eickelberg et al, 2001;Fornoni et al, 2001;Waller et al, 2004); inhibition of MMP activity (Fornoni et al, 2001;Chiu et al, 2009;Saygili et al, 2009) Leflunomide Pyrimidine synthesis inhibitor (Fukushima et al, 2007) Inhibitory effect on fibrogenesis (Yao et al, 2004;Si et al, 2007) Methotrexate Inhibitor of dihydrofolate reductase (Warren et al, 2008) Reduction of type IV collagen synthesis and ECM expansion (Yozai et al, 2005); influence on MMP and TIMP production …”

“…Inhibition of specific MMPs (Sutton et al, 2005;Machado et al, 2006) Cytokine modulators Etanercept Inhibition of TNF-␣ receptor (Moreland, 1999) Modulation of type II collagen synthesis and degradation (Briot et al, 2008) Infliximab, adalimumab Other drugs ACE-inhibitors e.g., Captopril, enalapril and numerous other ones Blocking of angiotensin converting enzyme (Johnston and Jackson, 1983) Modulation of collagen and proteoglycan synthesis and fibrosis (Kaneto et al, 1994;Cruz et al, 2000;Wapstra et al, 2001); influence on MMPs (Rizzoni et al, 2004;Aoki et al, 2007;Okada et al, 2008) ATR-blockers e.g., Losartan and numerous other ones Blocking of angiotensin II receptor (Gavras and Salerno, 1996) Upregulation of thrombospondin-1 expression (Fischer et al, 2001); downregulation of fibronectin expression (Fischer et al, 2001); inhibition of CTGF and fibrosis (Rupérez et al, 2003); inhibition of specific MMPs and TIMPs (Masutomo et al, 2001;Saygili et al, 2009) Calcium channel blockers e.g., Amlodipine, felodipine, diltiazem, and verapamil…”

“…Furthermore, it also represents a proof of the principle that hereditary diseases, including hereditary ECM diseases, can be treated with proper drugs downstream of the genetic lesion, if the pathogenetic mechanism is understood (Olsen, 2008). Besides being a curative agent for Ullrich congenital muscular dystrophy and Bethlem myopathy, cyclosporine A can beneficially contribute to ECM remodelling by regulating the activity of specific MMPs (Chiu et al, 2009;Saygili et al, 2009). These examples highlight the point that the mechanisms driving fibrogenesis are not necessarily the same as those regulating inflammation (Wynn, 2007(Wynn, , 2008; Sivakumar and Das, 2008) and that there is a specific need to develop drugs targeting the ECM besides developing better drugs for various inflammatory diseases.…”

Age-related regional differences in cardiac nerve growth factor expression

“…"n" represents the number of cell preparations. Neonatal rat atrial and ventricular myocytes (NRCM) were isolated and cultured as described previously Saygili et al 2009). Each NRCM cell preparation included 25-30 neonatal rats.…”

Angiotensin II–Induced MMP-2 Activity and MMP-14 and Basigin Protein Expression Are Mediated via the Angiotensin II Receptor Type 1–Mitogen-Activated Protein Kinase 1 Pathway in Retinal Pigment Epithelium

“…71,72 MMP-14 and BSG, major regulators of MMP-2 activity, [73][74][75] are considered candidate downstream effectors of Ang II. Several reports have demonstrated that Ang II positively regulates MMP-2 activity 18,76,77 and that MMP-14 in combination with BSG is involved in MMP-2 activation in ARPE-19 cells. 38 Using a pharmacologic approach combined with siRNA technology, it was demonstrated that Ang II stimulates MMP-2 activity, and MMP-14 and BSG protein expression via AT1 by signaling through ERK and p38 MAPKs in cultured RPE cells.…”