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LV wall rupture in the mouse occurs within a narrow time-window after AMI and is strain- and gender-dependent. Infarct expansion, regional hemorrhage with formation of hematoma and leuocyte accumulation are important pathological changes leading to reduced myocardial tensile strength.

LV remodeling and dysfunction in mice with MI are time-dependent processes and early remodeling seems associated with high risk of rupture and acute pump failure. Our findings provide a baseline description of this murine model and confirm echocardiography as a reliable means to serially assess changes of cardiac structure and function after MI.

Objective-Myocardial infarction (MI) is a serious complication of atherosclerosis associated with increasing mortality attributable to heart failure. Activation of phosphoinositide 3-kinase [PI3K(p110␣)] is considered a new strategy for the treatment of heart failure. However, whether PI3K(p110␣) provides protection in a setting of MI is unknown, and PI3K(p110␣) is difficult to target because it has multiple actions in numerous cell types. The goal of this study was to assess whether PI3K(p110␣) is beneficial in a setting of MI and, if so, to identify cardiac-selective microRNA and mRNA that mediate the protective properties of PI3K(p110␣). Methods and Results-Cardiomyocyte-specific transgenic mice with increased or decreased PI3K(p110␣) activity (caPI3K-Tg and dnPI3K-Tg, respectively) were subjected to MI for 8 weeks. The caPI3K-Tg subjected to MI had better cardiac function than nontransgenic mice, whereas dnPI3K-Tg had worse function. Using microarray analysis, we identified PI3K-regulated miRNA and mRNA that were correlated with cardiac function, including growth factor receptor-bound 14. Growth factor receptor-bound 14 is highly expressed in the heart and positively correlated with PI3K(p110␣) activity and cardiac function. Mice deficient in growth factor receptor-bound 14 have cardiac dysfunction. Conclusion-Activation of PI3K(p110␣) protects the heart against MI-induced heart failure. Cardiac-selective targets that mediate the protective effects of PI3K(p110␣) represent new drug targets for heart failure.

Objective-The goal of this study was to investigate the role of platelets in systemic and cardiac inflammatory responses and the development of postinfarct ventricular complications, as well as the efficacy of antiplatelet interventions. Methods and Results-Using a mouse myocardial infarction (MI) model, we determined platelet accumulation and severity of inflammation within the infarcted myocardium by immunohistochemistry and biochemical assays, analyzed peripheral blood platelet-leukocyte conjugation using flow cytometry, and tested antiplatelet interventions, including thienopyridines and platelet depletion. Platelets accumulated within the infarcted region early post-MI and colocalized with inflammatory cells. MI evoked early increase in circulating platelet-leukocyte conjugation mediated by P-selectin/P-selectin glycoprotein ligand-1. Antiplatelet interventions inhibited platelet-leukocyte conjugation in peripheral blood, inflammatory infiltration, content of matrix metalloproteinases or plasminogen activation, and expression of inflammatory mediators in the infarcted myocardium (all PϽ0.05) and lowered rupture incidence (PϽ0.01). Clopidogrel therapy alleviated the extent of chronic ventricular dilatation by serial echocardiography. Key Words: ischemic heart disease Ⅲ leukocytes Ⅲ platelets Ⅲ thienopyridines Ⅲ inflammation Ⅲ myocardial infarction Ⅲ ventricular rupture T he role of platelets in atherosclerotic lesions and acute coronary syndrome has been well documented. The proinflammatory actions of platelets have received increasing attention. 1,2 Platelets contribute to inflammatory responses through release of inflammatory mediators and plateletleukocyte interactions by which platelets mediate leukocyte activation and infiltration into inflamed tissues. 1,2 There are several reports of an elevated proportion of platelet-leukocyte aggregates tested ex vivo in blood samples from patients with acute coronary syndromes. [3][4][5] The current rationale for routine use of the platelet P2Y 12 receptor inhibitors thienopyridines (clopidogrel and prasugrel) is to prevent arterial thrombosis following coronary intervention. 6 Thienopyridine treatment is known to inhibit platelet-leukocyte interactions in the peripheral blood of patients with peripheral atherosclerotic vascular disease, coronary artery disease, or renal transplantation. 5,6 Myocardial infarction (MI) evokes intense inflammatory responses both systemically and within the infarcted myocardium, with adverse consequences. 7 The potential contribution of platelets to postinfarct cardiac inflammation remains unexplored. Relevant to this is the question of whether thienopyridines exert cardiac protection through inhibition of platelet's inflammatory action in the infarcted myocardium, independent of vascular thrombosis. Conclusion-PlateletsVentricular wall rupture is a fatal complication of acute MI, with a death rate of 70% to 90%. 8,9 Recent experimental studies, including ours, have provided strong evidence that wall rupture is the consequence o...

BACKGROUND AND PURPOSEWhile maintaining cardiac performance, chronic b-adrenoceptor activation eventually exacerbates the progression of cardiac remodelling and failure. We examined the adverse signalling pathways mediated by nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS) after chronic b2-adrenoceptor activation. EXPERIMENTAL APPROACHMice with transgenic b2-adrenoceptor overexpression (b2-TG) and non-transgenic littermates were either untreated or treated with an antioxidant (N-acetylcysteine, NAC) or NADPH oxidase inhibitors (apocynin, diphenyliodonium). Levels of ROS, phosphorylated p38 mitogen-activated protein kinase (MAPK), pro-inflammatory cytokines and collagen content in the left ventricle (LV) and LV function were measured and compared. KEY RESULTSb2-TG mice showed increased ROS production, phosphorylation of p38 MAPK and heat shock protein 27 (HSP27), expression of pro-inflammatory cytokines and collagen, and progressive ventricular dysfunction. b2-adrenoceptor stimulation similarly increased ROS production and phosphorylation of p38 MAPK and HSP27 in cultured cardiomyocytes. Treatment with apocynin, diphenyliodonium or NAC reduced phosphorylation of p38 MAPK and HSP27 in both cultured cardiomyocytes and the LV of b2-TG mice. NAC treatment (500 mg·kg) for 2 weeks eliminated the up-regulated expression of pro-inflammatory cytokines and collagen in the LV of b2-TG mice. Chronic NAC treatment to b2-TG mice from 7 to 10 months of age largely prevented progression of ventricular dilatation, preserved contractile function (fractional shortening 37 Ϯ 5% vs. 25 Ϯ 3%, ejection fraction 52 Ϯ 5% vs. 32 Ϯ 4%, both P < 0.05), reduced cardiac fibrosis and suppressed matrix metalloproteinase activity. CONCLUSION AND IMPLICATIONSb2-adrenoceptor stimulation provoked NADPH oxidase-derived ROS production in the heart. Elevated ROS activated p38 MAPK and contributed significantly to cardiac inflammation, remodelling and failure. Abbreviations a-MHC, a-myosin heavy chain; a-SMA, a-smooth muscle actin; b2-TG, b2-adrenoceptor transgenic; CMH, 1-hydroxy-3-methoxycarbonyl-2,2,5,5,tetramethylpyrrolidine; CTGF, connective tissue growth factor; DHE, BJP British Journal of Pharmacology LINKED ARTICLE

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In the setting of myocardial infarction (MI), implanted stem cell viability is low and scar formation limits stem cell homing, viability, and integration. Thus, interventions that favorably remodel fibrotic healing may benefit stem cell therapies. However, it remains unclear whether it is feasible and safe to remodel fibrotic healing post-MI without compromising ventricular remodeling and dysfunction. This study, therefore, determined the anti-fibrotic and other effects of the hormone, relaxin in a mouse model of MI. Adult male mice underwent left coronary artery ligation-induced MI and were immediately treated with recombinant human relaxin (MI þ RLX) or vehicle (MI þ VEH) over 7 or 30 days, representing time points of early and mature fibrotic healing. Cardiac function was assessed by echocardiography and catheterization, while comprehensive immunohistochemistry, morphometry, and western blotting were performed to explore the relaxin-induced mechanisms of action post-MI. RLX significantly inhibited the MI-induced progression of cardiac fibrosis over 7 and 30 days, which was associated with a reduction in TGF-b1 expression, myofibroblast differentiation, and cardiomyocyte apoptosis in addition to a promotion of matrix metalloproteinase-13 levels and de novo blood vessel growth (all Po0.05 vs respective measurements from MI þ VEH mice). Despite the evident fibrotic healing post-MI, relaxin did not adversely affect the incidence of ventricular free-wall rupture or the extent of LV remodeling and dysfunction. These combined findings demonstrate that RLX favorably remodels the process of fibrotic healing post-infarction by lowering the density of mature scar tissue in the infarcted myocardium, border zone, and non-infarcted myocardium, and may, therefore, facilitate cell-based therapies in the setting of ischemic heart disease.