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Articles by J. M Penninger
Total Records ( 5 ) for J. M Penninger
  P Blyszczuk , G Kania , T Dieterle , R. R Marty , A Valaperti , C Berthonneche , T Pedrazzini , C. T Berger , S Dirnhofer , C. M Matter , J. M Penninger , T. F Luscher and U. Eriksson
 

Rationale: The myeloid differentiation factor (MyD)88/interleukin (IL)-1 axis activates self–antigen-presenting cells and promotes autoreactive CD4+ T-cell expansion in experimental autoimmune myocarditis, a mouse model of inflammatory heart disease.

Objective: The aim of this study was to determine the role of MyD88 and IL-1 in the progression of acute myocarditis to an end-stage heart failure.

Methods and Results: Using -myosin heavy chain peptide (MyHC-)–loaded, activated dendritic cells, we induced myocarditis in wild-type and MyD88–/– mice with similar distributions of heart-infiltrating cell subsets and comparable CD4+ T-cell responses. Injection of complete Freund’s adjuvant (CFA) or MyHC-/CFA into diseased mice promoted cardiac fibrosis, induced ventricular dilation, and impaired heart function in wild-type but not in MyD88–/– mice. Experiments with chimeric mice confirmed the bone marrow origin of the fibroblasts replacing inflammatory infiltrates and showed that MyD88 and IL-1 receptor type I signaling on bone marrow–derived cells was critical for development of cardiac fibrosis during progression to heart failure.

Conclusions: Our findings indicate a critical role of MyD88/IL-1 signaling in the bone marrow compartment in postinflammatory cardiac fibrosis and heart failure and point to novel therapeutic strategies against inflammatory cardiomyopathy.

  D Guo , Z Kassiri , R Basu , F. L Chow , V Kandalam , F Damilano , W Liang , S Izumo , E Hirsch , J. M Penninger , P. H Backx and G. Y. Oudit
  Rationale:

Mechanotransduction and the response to biomechanical stress is a fundamental response in heart disease. Loss of phosphoinositide 3-kinase (PI3K), the isoform linked to G protein–coupled receptor signaling, results in increased myocardial contractility, but the response to pressure overload is controversial.

Objective:

To characterize molecular and cellular responses of the PI3K knockout (KO) mice to biomechanical stress.

Methods and Results:

In response to pressure overload, PI3KKO mice deteriorated at an accelerated rate compared with wild-type mice despite increased basal myocardial contractility. These functional responses were associated with compromised phosphorylation of Akt and GSK-3. In contrast, isolated single cardiomyocytes from banded PI3KKO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3KKO mice. β-Adrenergic stimulation increased cAMP levels with increased phosphorylation of CREB, leading to increased expression of cAMP-responsive matrix metalloproteinases (MMPs), MMP2, MT1-MMP, and MMP13 in cardiomyocytes and cardiofibroblasts. Loss of PI3K resulted in increased cAMP levels with increased expression of MMP2, MT1-MMP, and MMP13 and increased MMP2 activation and collagenase activity in response to biomechanical stress. Selective loss of N-cadherin from the adhesion complexes in the PI3KKO mice resulted in reduced cell adhesion. The β-blocker propranolol prevented the upregulation of MMPs, whereas MMP inhibition prevented the adverse remodeling with both therapies, preventing the functional deterioration in banded PI3KKO mice. In banded wild-type mice, long-term propranolol prevented the adverse remodeling and systolic dysfunction with preservation of the N-cadherin levels.

Conclusions:

The enhanced propensity to develop heart failure in the PI3KKO mice is attributable to a cAMP-dependent upregulation of MMP expression and activity and disorganization of the N-cadherin/β-catenin cell adhesion complex. β-Blocker therapy prevents these changes thereby providing a novel mechanism of action for these drugs.

  Z Kassiri , J Zhong , D Guo , R Basu , X Wang , P. P Liu , J. W Scholey , J. M Penninger and G. Y. Oudit
 

Background— Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes Ang II into Ang 1-7, thereby functioning as a negative regulator of the renin-angiotensin system. We hypothesized that ACE2 deficiency may compromise the cardiac response to myocardial infarction (MI).

Methods and Results— In response to MI (induced by left anterior descending artery ligation), there was a persistent increase in ACE2 protein in the infarct zone in wild-type mice, whereas loss of ACE2 enhanced the susceptibility to MI, with increased mortality, infarct expansion, and adverse ventricular remodeling characterized by ventricular dilation and systolic dysfunction. In ACE2-deficient hearts, elevated myocardial levels of Ang II and decreased levels of Ang 1-7 in the infarct-related zone was associated with increased production of reactive oxygen species. ACE2 deficiency leads to increased matrix metalloproteinase (MMP) 2 and MMP9 levels with MMP2 activation in the infarct and peri-infarct regions, as well as increased gelatinase activity leading to a disrupted extracellular matrix structure after MI. Loss of ACE2 also leads to increased neutrophilic infiltration in the infarct and peri-infarct regions, resulting in upregulation of inflammatory cytokines, interferon-, interleukin-6, and the chemokine, monocyte chemoattractant protein-1, as well as increased phosphorylation of ERK1/2 and JNK1/2 signaling pathways. Treatment of Ace2/y-MI mice with irbesartan, an AT1 receptor blocker, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, infarct size, MMP activation, and myocardial inflammation, ultimately resulting in improved post-MI ventricular function.

Conclusions— We conclude that loss of ACE2 facilitates adverse post-MI ventricular remodeling by potentiation of Ang II effects by means of the AT1 receptors, and supplementing ACE2 can be a potential therapy for ischemic heart disease.

  A. E Awad , V Kandalam , S Chakrabarti , X Wang , J. M Penninger , S. T Davidge , G. Y Oudit and Z. Kassiri
 

Tumor necrosis factor (TNF) is an inflammatory cytokine that is upregulated in a number of cardiomyopathies. Adverse cardiac remodeling and dilation result from degradation of the extracellular matrix by matrix metalloproteinases (MMPs). We investigated whether TNF can directly trigger expression and activation of MMPs in cardiac cells. We compared MMP expression profile and activities between primary cultures of mouse neonatal cardiomyocytes and cardiofibroblasts and in cellular and extracellular compartments. In response to recombinant TNF (rTNF, 20 ng/ml), cardiomyocytes exhibited faster and more pronounced superoxide production compared with cardiofibroblasts, concomitant with increased expression of several MMPs. MMP9 levels increased more rapidly and about twofold more in cardiomyocytes than in cardiofibroblasts. TNF did not induce MMP2 expression. Expression of collagenases (MMP8, MMP12, MMP13, and MMP14) increased significantly, while total collagenase activity increased to a greater degree in conditioned medium of cardiomyocytes than in cardiofibroblasts. rTNF-mediated MMP expression and activation were dependent on superoxide production and were blocked by apocynin, an NADPH oxidase inhibitor. We identified phosphatidylinositol 3-kinase (PI3K) as a key factor in TNF-mediated events since TNF-induced superoxide production, MMP expression, and activity were significantly suppressed in cardiomyocytes and cardiofibroblasts deficient in PI3K. We further demonstrated that the TNF-superoxide-MMP axis of events is in fact activated in heart disease in vivo. Wild-type and TNF–/– mice subjected to cardiac pressure overload revealed that TNF deficiency resulted in reduced superoxide levels, collagenase activities, PI3K activity, and fibrosis leading to attenuated cardiac dilation and dysfunction. Our study demonstrates that TNF triggers expression and activation of MMPs faster and stronger in cardiomyocytes than in cardiofibroblasts in a superoxide-dependent manner and via activation of PI3K, thereby contributing to adverse myocardial remodeling in disease.

  T Nagatake , S Fukuyama , D. Y Kim , K Goda , O Igarashi , S Sato , T Nochi , H Sagara , Y Yokota , A. M Jetten , T Kaisho , S Akira , H Mimuro , C Sasakawa , Y Fukui , K Fujihashi , T Akiyama , J. i Inoue , J. M Penninger , J Kunisawa and H. Kiyono
 

The eye is protected by the ocular immunosurveillance system. We show that tear duct–associated lymphoid tissue (TALT) is located in the mouse lacrimal sac and shares immunological characteristics with mucosa-associated lymphoid tissues (MALTs), including the presence of M cells and immunocompetent cells for antigen uptake and subsequent generation of mucosal immune responses against ocularly encountered antigens and bacteria such as Pseudomonas aeruginosa. Initiation of TALT genesis began postnatally; it occurred even in germ-free conditions and was independent of signaling through organogenesis regulators, including inhibitor of DNA binding/differentiation 2, retinoic acid–related orphan receptor t, lymphotoxin (LT) 1β2–LTβR, and lymphoid chemokines (CCL19, CCL21, and CXCL13). Thus, TALT shares immunological features with MALT but has a distinct tissue genesis mechanism and plays a key role in ocular immunity.

 
 
 
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