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Molecular cues guiding inflammatory responses

Barreiro O et al. Cardiovasc Res (2010) 86(2): 174-182 first published online January 6, 2010 doi:10.1093/cvr/cvq001 - Click here to view the abstract

Schematic view of chemokine-dependent migration of specialized immune cell subsets to inflammatory foci.

The differential expression of cell adhesion molecules and chemokines and their receptors plays a key role in the selective recruitment of leucocytes to inflamed sites or in their re-circulation to maintain homeostasis. After infection by pathogens or during inflammation, myeloid subsets generated in the bone marrow can be directed to inflamed non-lymphoid tissues after the up-regulation of several chemokine receptors, uptake the antigens, and then migrate to the lymph nodes to activate lymphoid cells. In these organs, differentiation and activation of helper T cells and/or regulatory T cells takes place, up-regulating specific chemokine receptors and directing their migration to the inflamed tissue. Once in the inflamed tissue, different subsets of helper T cells play an essential role in antiviral, allergic, and immune responses to extracellular pathogens, whereas regulatory T cells play a key role in the modulation of the immune response after an inflammatory process or in maintaining immune tolerance after antigen elimination. The regulatory mechanism of cell migration is critical to mount a proper immune response in the inflamed tissue, with participation of both the innate and adaptive immunity.

The role of the protein degradation systems in viral myocarditis leading to dilated cardiomyopathy

Luo H et al. Cardiovasc Res (2010) 85(2): 347-356 first published online July 3, 2009 doi:10.1093/cvr/cvp225 - Click here to view the abstract

Viral myocarditis is an inflammatory disease of the myocardium caused by virus infection. The disease progression occurs in three distinct stages: viral infection, immune response, and cardiac remodelling. Recent evidence suggests that the host proteolytic systems play crucial roles in the regulation of the pathogenesis of viral myocarditis in all three stages. During the viral infection stage, the virus evolves different strategies to utilize the host ubiquitin/proteasome system and the autophagy machinery to facilitate its replication. At the immune response stage, viral infection induces the formation of an immunoproteasome to increase MHC class I antigen presentation. Meanwhile, production of pro-inflammatory cytokines is enhanced, partially through the ubiquitin/proteasome system-mediated NFκB activation. Autophagy may also contribute to immune-mediated pathogenesis by modulating MHC class II antigen presentation. During the cardiac remodelling phase, increased accumulation of abnormal ubiquitin-protein conjugates/aggregates and elevated oxidative stress lead to the eventual impairment of the ubiquitin/proteasome function, subsequently resulting in abnormal regulation of contractile apparatus expression and also triggering apoptosis and autophagic cell death. As a result of myocyte loss and decreased contractile properties, the left ventricle of the heart begins to dilate to compensate for impaired cardiac function.

Proteins mediating collagen biosynthesis and accumulation in arterial repair: novel targets for anti-restenosis therapy

Osherov AB et al. Cardiovasc Res (2011) 91(1): 16-26 doi:10.1093/cvr/cvr012 - Click here to view the abstract

Effects of matrix metalloproteinases (MMPs) in the vessel wall.

Proteins mediating collagen biosynthesis and accumulation in arterial repair: novel targets for anti-restenosis therapy

Osherov AB et al. Cardiovasc Res (2011) 91(1): 16-26 doi:10.1093/cvr/cvr012 - Click here to view the abstract

Receptor signaling pathways affecting extracellular matrix synthesis in the arterial wall in response to vascular injury. See text for details. Red arrow indicates inhibition, green arrow indicates activation, yellow arrow indicates signal transduction to the nucleus. VSMC, vascular smooth muscle cell. TGF-β, transforming growth factor beta, PDGF, platelet-derived growth factor. MMPs, matrix metalloproteinases, ET, endothelin.

Disruption of fuel servicing in the myocardium: from ‘eutaxy and efficiency’ to ‘ataxy and inefficiency’

Saikawa T Cardiovasc Res (2011) 92(1): 3-4 doi:10.1093/cvr/cvr231 - Click here to view the abstract

Deletion of PGC-1β leads to disruption of mitohormesis and arrhythmias in cardiomyocytes.
A tentative scheme is shown that depicts how PPAR-γ or PGC-1s stimulation and suppression modulate electrical activity in cardiomyocytes. For biological activity, PPAR-γ needs coactivation by PGC-1α/β. These coactivators are inducible and play a vital role in cellular ATP production and mitochondrial function.
Exogenous stress stimulates the expression of chemokines and adhesion molecules in the heart. These molecules promote atrial fibrosis on the one hand, and macrophage recruitment and inflammation on the other, which result in heart failure and arrhythmias substrate formation.
The suppression or deletion of PGC-1β seems to result in variable electrical instabilities and arrhythmias, especially during adrenergic stress. An imbalance of mitochondrial ATP production is noted as well, which is arrhythmogenic by itself. The stimulation of PPARγ; blocks stress-induced expression of chemokines and adhesion molecules. The recruitment of macrophages from storage sites such as splenic red pulp (red bar) is also suppressed, resulting in an improvement of atrial fibrosis and mitochondrial function. Details of signaling cascades mediated by the PPARγ-PGC-1 axis that leads to electrical instability are waiting to be elucidated.