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Background Extracellular matrix (ECM) turnover plays an important role in left ventricular (LV) remodelling following myocardial infarction (MI). Cysteinyl cathepsins contribute to ECM catabolism in arterial diseases, suggesting their participation in post-MI remodelling. Methods and results Left anterior descending artery ligation-induced MI in mice showed increased expression and activity of cathepsin S (CatS). Administration of a non-selective cathepsin inhibitor, E64d, aggravated LV dysfunction at 7 and 28 days post-MI. Mechanistic studies showed that E64d increased post-MI inflammatory cell accumulation and cytokine expression, but did not affect apoptosis or angiogenesis in infarcted myocardium. Furthermore, E64d suppressed TGF-β1-induced Smad2 and Smad3 activation and expression of fibronectin extra domain A (ED-A), an alternatively spliced fibronectin variant, and subsequently prevented cardiac fibroblast trans-differentiation into myofibroblast, which contributed to post-MI collagen and fibronectin synthesis and deposition. Consistently, selective inhibition or genetically determined deficiency of CatS also reduced myocardial Smad2 and Smad3 activation and ED-A fibronectin expression, thus suppressing fibroblast trans-differentiation and resulting in adverse collagen turnover and impaired cardiac function—recapitulating the findings in mice treated with E64d. Conclusion Along with its established activities in ECM degradation, CatS plays novel roles in TGF-β1 signalling, myofibroblast trans-differentiation, and ECM protein synthesis, thereby regulating scar formation in the infarcted myocardium and preserving LV function after experimental MI. [ABSTRACT FROM AUTHOR]

Abstract Background Extracellular matrix metabolism and cardiac cell death participate centrally in myocardial infarction (MI). This study tested the roles of collagenolytic cathepsin K (CatK) in post-MI left ventricular remodeling. Methods and results Patients with acute MI had higher plasma CatK levels (20.49 ± 7.07 pmol/L, n = 26) than those in subjects with stable angina pectoris (8.34 ± 1.66 pmol/L, n = 28, P =.01) or those without coronary heart disease (6.63 ± 0.84 pmol/L, n = 93, P =.01). CatK protein expression increases in mouse hearts at 7 and 28 days post-MI. Immunofluorescent staining localized CatK expression in cardiomyocytes, endothelial cells, fibroblasts, macrophages, and CD4+ T cells in infarcted mouse hearts at 7 days post-MI. To probe the direct participation of CatK in MI, we produced experimental MI in CatK-deficient mice (Ctsk −/− ) and their wild-type (Ctsk +/+ ) littermates. CatK-deficiency yielded worsened cardiac function at 7 and 28 days post-MI, compared to Ctsk +/+ littermates (fractional shortening percentage: 5.01 ± 0.68 vs. 8.62 ± 1.04, P <.01, 7 days post-MI; 4.32 ± 0.52 vs. 7.60 ± 0.82, P <.01, 28 days post-MI). At 7 days post-MI, hearts from Ctsk −/− mice contained less CatK-specific type-I collagen fragments (10.37 ± 1.91 vs. 4.60 ± 0.49 ng/mg tissue extract, P =.003) and more fibrosis (1.67 ± 0.93 vs. 0.69 ± 0.20 type-III collagen positive area percentage, P =.01; 14.25 ± 4.12 vs. 6.59 ± 0.79 α-smooth muscle actin-positive area percentage, P =.016; and 0.82 ± 0.06 vs. 0.31 ± 0.08 CD90-positive area percentage, P =.008) than those of Ctsk +/+ mice. Immunostaining demonstrated that CatK-deficiency yielded elevated cardiac cell death but reduced cardiac cell proliferation. In vitro studies supported a role of CatK in cardiomyocyte survival. Conclusion Plasma CatK levels are increased in MI patients. Heart CatK expression is also elevated post-MI, but CatK-deficiency impairs post-MI cardiac function in mice by increasing myocardial fibrosis and cardiomyocyte death. Highlights • Plasma levels of CatK increase in patients with CHD particularly during AMI, compared to controls. • CatK is expressed in cardiomyocytes, endothelial cell, fibroblast, macrophage, and CD4+ T-cell from post-MI mouse heart. • In post-MI heart, CatK-deficiency increases fibrosis and cell death, and impairs cell proliferation and cardiac function. • CatK inhibition or deficiency increases cardiomyocyte death, but suppresses CD4+ T-cell and macrophage death. [ABSTRACT FROM AUTHOR]

IgE has a key role in the pathogenesis of allergic responses through its ability to activate mast cells via the receptor FcεR1. In addition to mast cells, many cell types implicated in atherogenesis express FcεR1, but whether IgE has a role in this disease has not been determined. Here, we demonstrate that serum IgE levels are elevated in patients with myocardial infarction or unstable angina pectoris. We found that IgE and the FcεR1 subunit FcεR1α were present in human atherosclerotic lesions and that they localized particularly to macrophage-rich areas. In mice, absence of FcεR1α reduced inflammation and apoptosis in atherosclerotic plaques and reduced the burden of disease. In cultured macrophages, the presence of TLR4 was required for FcεR1 activity. IgE stimulated the interaction between FcεR1 and TLR4, thereby inducing macrophage signal transduction, inflammatory molecule expression, and apoptosis. These IgE activities were reduced in the absence of FcεR1 or TLR4. Furthermore, IgE activated macrophages by enhancing Na+/H+ exchanger 1 (NHE1) activity. Inactivation of NHE1 blocked IgE-induced macrophage production of inflammatory molecules and apoptosis. Cultured human aortic SMCs (HuSMCs) and ECs also exhibited IgE-induced signal transduction, cytokine expression, and apoptosis. In human atherosclerotic lesions, SMCs and ECs colocalized with IgE and TUNEL staining. This study reveals what we believe to be several previously unrecognized IgE activities that affect arterial cell biology and likely other IgE-associated pathologies in human diseases. [ABSTRACT FROM AUTHOR]