Potential therapeutic targets for cardiac fibrosis: TGFbeta, angiotensin, endothelin, CCN2, and PDGF, partners in fibroblast activation.
Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, "activated" fibroblasts migrate into the wound area, where they synthesize and remodel newly created extracellular matrix. The specialized type of fibroblast responsible for this action is the alpha-smooth muscle actin (alpha-SMA)-expressing myofibroblast. Abnormal persistence of the myofibroblast is a hallmark of fibrotic diseases. Proteins such as transforming growth factor (TGF)beta, endothelin-1, angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to myofibroblast differentiation and persistence. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGFbeta, endothelin-1, Ang II, CCN2, and PDGF and to fibroblast activation in tissue repair and fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of cardiac fibrosis.
Dental Sciences Building, London ON N6A 5C1, Canada. Andrew.Leask@schulich.uwo.ca
Andrew
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Leask
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002317:Cardiovascular Agents / Q000494:pharmacology / Q000627:therapeutic use; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D015195:Drug Design; D019332:Endothelin-1 / Q000378:metabolism*; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D006331:Heart Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D002317:Cardiovascular Agents; D019332:Endothelin-1; D016326:Extracellular Matrix Proteins; D010982:Platelet-Derived Growth Factor; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D055513:Connective Tissue Growth Factor