Signaling Mechanisms Regulating Fibroblast Activation, Phenoconversion and Fibrosis in the Heart.

Cardiac fibroblasts (CFs) maintain the cardiac extracellular matrix (ECM) through myocardial remodelling. The remodelling process can become dysregulated during various forms of heart disease  which leads to an overall accumulation of ECM. This results in cardiac fibrosis which increases the risk of heart failure in many patients. During heart disease, quiescent CFs undergo phenoconversion to an activated cell type called cardiac myofibroblasts (CMFs). Factors influencing phenoconversion include transforming growth factor β (TGF-β) which via SMADs (small mothers against decapentaplegic) activates the myofibroblast marker gene αSMA (α smooth muscle actin). Signaling molecules as diverse as NAD(P)H oxidase 4 (Nox4) and Wnt have been found to interact with TGF-β signalling via SMADs. Pathways, including FAK/TAK/JNK and PI3K/Akt/rac have also been implicated in activating phenoconversion of fibroblasts. Another major contributor is mechanical stress exerted on CFs by ECM changes, which involves activation of ERK and subsequent αSMA expression. Other factors, such as the mast cell protease tryptase and the seeding density also affect the phenoconversion of fibroblast cultures in vitro. Further, reversal of myofibroblast phenotype has been reported by a negative regulator of TGF-β, Ski, as well as the hormone relaxin and the second messenger cAMP. Targeting the signaling molecules involved in promoting phenoconversion of CFs to CMFs presents a possible method of controlling cardiac fibrosis. Here, we provide a brief review of signaling mechanisms responsible for phenoconversion and identify critical targets for the treatment of cardiac fibrosis.

Myocardial affection in mice infected with Schistosoma mansoni: histopathologic and immunofluorescent observations

20 Swiss albino mice were exposed to cercarial infection of Schistosoma mansoni shedded from Biomphalaria Alexandrina snails. A group of non-infected mice were used as negative controls. An animal was sacrificed every 2 weeks from the 8[th] week following infection till the 46[th] week. Hearts of both groups were removed and specimens were sent for light microscopic and direct immunofluorescent examination. Histopathologic study revealed granulomatous schistosomatic myocarditis in 3 mice. There were no muscle fibre degeneration or attenuation, no interstitial fibrosis or mononuclear cell infiltration [apart from the schistosomal granulomas] and no endocardial affection. Vascular immunofluorescence for schistosomal egg antigen [SEA] was observed in 6 mice. The reaction was linear involving one or more layers of the coating wall. Positive immunofluorescence for SEA appeared also within the granulomatous reaction in the hearts of the 3 affected mice. No specific immunofluorescent deposits were detected over the myofibers in the infected group at any stage of infection. Thus, myocardial affection in mice infected with schistosoma mansoni was minimal. The relevance of these results to other studies and to observations in schistosomal patients was discussed