Rationale: The extracellular matrix may induce detrimental inflammatory responses on degradation, causing adverse cardiac remodeling and heart failure. The extracellular matrix protein fibronectin... Show moreRationale: The extracellular matrix may induce detrimental inflammatory responses on degradation, causing adverse cardiac remodeling and heart failure. The extracellular matrix protein fibronectin-EDA (EIIIA; EDA) is upregulated after tissue injury and may act as a "danger signal" for leukocytes to cause adverse cardiac remodeling after infarction. Objective: In the present study, we evaluated the role of EDA in regulation of postinfarct inflammation and repair after myocardial infarction. Methods and Results: Wild-type and EDA(-/-) mice underwent permanent ligation of the left anterior coronary artery. Despite equal infarct size between groups (38.2+/-4.6% versus 38.2+/-2.9% of left ventricle; P=0.985), EDA(-/-) mice exhibited less left ventricular dilatation and enhanced systolic performance compared with wild-type mice as assessed by serial cardiac MRI measurements. In addition, EDA(-/-) mice exhibited reduced fibrosis of the remote area without affecting collagen production, cross-linking, and deposition in the infarct area. Subsequently, ventricular contractility and relaxation was preserved in EDA(-/-). At tissue level, EDA(-/-) mice showed reduced inflammation, metalloproteinase 2 and 9 activity, and myofibroblast transdifferentiation. Bone marrow transplantation experiments revealed that myocardium-induced EDA and not EDA from circulating cells regulates postinfarct remodeling. Finally, the absence of EDA reduced monocyte recruitment as well as monocytic Toll-like receptor 2 and CD49d expression after infarction. Conclusions: Our study demonstrated that parenchymal fn-EDA plays a critical role in adverse cardiac remodeling after infarction. Absence of fn-EDA enhances survival and cardiac performance by modulating matrix turnover and inflammation via leukocytes and fibroblasts after infarction. (Circ Res. 2011; 108: 582-592.) Show less
Bongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA, Steendijk P, Doevendans PA, Joles JA. The nitric oxide donor molsidomine rescues cardiac function in rats with chronic... Show moreBongartz LG, Braam B, Verhaar MC, Cramer MJ, Goldschmeding R, Gaillard CA, Steendijk P, Doevendans PA, Joles JA. The nitric oxide donor molsidomine rescues cardiac function in rats with chronic kidney disease and cardiac dysfunction. Am J Physiol Heart Circ Physiol 299: H2037-H2045, 2010. First published September 17, 2010; doi: 10.1152/ajpheart.00400.2010.-We recently developed a rat model of cardiorenal failure that is characterized by severe left ventricular systolic dysfunction (LVSD) and low nitric oxide (NO) production that persisted after temporary low-dose NO synthase inhibition. We hypothesized that LVSD was due to continued low NO availability and might be reversed by supplementing NO. Rats underwent a subtotal nephrectomy and were treated with low-dose NO synthase inhibition with N-omega-nitro-L-arginine up to week 8. After 3 wk of washout, rats were treated orally with either the long-acting, tolerance-free NO donor molsidomine (Mols) or vehicle (Veh). Cardiac and renal function were measured on weeks 11, 13, and 15. On week 16, LV hemodynamics and pressure-volume relationships were measured invasively, and rats were killed to quantify histological damage. On week 15, blood pressure was mildly reduced and creatinine clearance was increased by Mols (both P < 0.05). Mols treatment improved ejection fraction (53 +/- 3% vs. 37 +/- 2% in Veh-treated rats, P < 0.001) and stroke volume (324 +/- 33 vs. 255 +/- 15 mu 1 in Veh-treated rats, P < 0.05). Rats with Mols treatment had lower end-diastolic pressures (8.5 +/- 1.1 mmHg) than Veh-treated rats (16.3 +/- 3.5 mmHg, P < 0.05) and reduced time constants of relaxation (21.9 +/- 1.8 vs. 30.9 +/- 3.3 ms, respectively, P < 0.05). The LV end-systolic pressure-volume relationship was shifted to the left in Mols compared with Veh treatment. In summary, in a model of cardiorenal failure with low NO availability, supplementing NO significantly improves cardiac systolic and diastolic function without a major effect on afterload. Show less
