Linkage between elevated PDGF-C expression and myocardial fibrogenesis in coxsackievirus B3-induced chronic myocarditis.

Coxsackievirus B3 (CVB3) is the most common causative agent of myocarditis. Acute myocarditis caused by CVB3 infection either recovers completely without any functional and morphological defects or progresses to chronic myocarditis, which is characterized by chronic inflammation and interstitial hyperplasia that may be related to progressive intrinsic dysfunction, degeneration, and loss of cardiomyocyte viability. In later stages of this disease, CVB3 persists in the myocardium and results in chronic activation of fibroblasts and progressive fibrosis of the myocardium, reflected by the accumulation of connective tissue and extracellular matrix, which is characteristic of dilated cardiomyopathy (DCM). However, the molecular mechanisms by which acute myocarditis progresses to chronic myocarditis and DCM still remain unclear. Fibrotic diseases usually occur in a variety of organ systems including lung, liver, kidney, intestine, heart, skin, and bone marrow. Several polypeptide mediators are central to the fibrotic process, including interleukin-1 (IL-1), tumor necrosis factor-a (TNF-a), plateletderived growth factor (PDGF), and transforming growth factor-b1. They primarily function in fibrogenesis to transform interstitial fibroblasts into myofibroblasts and stimulate collagen deposition by newly replicated myofibroblasts. PDGF was discovered as a component of whole blood serum and initially purified from human platelets. It is well documented that PDGF, which acts primarily on connective tissue and is involved in cellular proliferation and tissue repair, is a potent mitogenic polypeptide and chemoattractant that functions as an important mediator in the pathogenesis of cardiovascular diseases. Grün et al. report a link between increased expression of PDGF to the development of myocardial fibrosis. The authors utilized a mouse model with immunodeficient major histocompatibititing complex (MHC) class II knockout and chronic myocarditis caused by CVB3 infection. Their data indicated that immunodeficient mice developed a higher titre of CVB3, prominent inflammatory cell infiltration, and moderately elevated expression of the inflammatory cytokines IL-1a, IL-1b, and TNF-a in mouse hearts, and showed severe cardiac fibrosis. The PDGF family consists of four isoforms (A, B, C, and D). These PDGF isoforms have a common structure with the typical growth factor domain involved in the dimerization of the two subunits and in receptor binding and activation. They exist as four disulfide-linked homodimeric proteins, PDGF-AA, PDGF-BB, PDGF-CC, and PDGF-DD, and one heterodimeric protein, PDGF-AB, and differentially bind homoand heterodimer combinations of two receptor tyrosine kinases, PDGF-Ra and PDGF-Rb. Both PDGF-A and PDGF-B chain dimeric isoforms (PDGF-AA, PDGF-AB, and PDGF-BB) have important roles in the pathogenesis of fibrosis. The roles of PDGF-C and PDGF-D in the cardiovascular system are just at the beginning of being explored; much less is known regarding the significance of the more recently discovered PDGF-C and PDGF-D isoforms to fibrogenesis. To explore which factor may play a major role in CVB3induced myocarditis and fibrosis, the study of Grün et al. demonstrated, using immunohistochemistry, PCR, and in situ hybridization, that all analysed isoforms of