Doxorubicin directly induced fibrotic change of cardiac fibroblasts

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  • Umemura Masanari
    Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine
  • Narikawa Masatoshi
    Department of Medical Science and Cardiorenal Medicine, Yokohama City University Graduate School of Medicine
  • Tanaka Ryo
    Yokosuka City Hospital
  • Nemoto Hiroko
    Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine
  • Nakakaji Rina
    Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine
  • Nagasako Akane
    Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine
  • Ishikawa Yoshihiro
    Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine

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Other Title
  • ドキソルビシンの心臓線維芽細胞に注目した心毒性メカニズムの解明と治療戦略
  • ドキソルビシン ノ シンゾウ センイガ サイボウ ニ チュウモク シタ シン ドクセイ メカニズム ノ カイメイ ト チリョウ センリャク

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<p>Doxorubicin (DOX)-induced cardiomyopathy has a poor prognosis. No early detection or effective treatment methods are available in clinical. The mechanisms of cardiotoxicity were considered as oxidative stress and apoptosis in cardiomyocytes. However, the effect of DOX on cardiac fibroblasts remains to be developed. We investigated the direct effect of DOX on the function of human cardiac fibroblasts (HCFs) independently of cell death pathway. Animal study showed that lower dose of DOX (4 mg/kg/week for 3 weeks, i.p.) than a toxic cumulate dose, induced perivascular fibrosis without cell death in hear of mice. DOX increased the protein expression of α-SMA (a marker of trans-differentiation) in HCFs culture cells, indicating that DOX promoted the trans-differentiation of HCFs into myofibroblast. DOX also increased the mRNA and protein expression of matrix metalloproteinase (MMP)-1 in less than 0.1 μM which did not induce cell apoptosis of HCFs cells via PI3K/Akt pathway in HCFs. DOX increased Interleukin-6 (IL-6) via transforming growth factor (TGF)-β/Smad pathway. In addition, DOX induced the mitochondrial damage and increased the expression of Interleukin-1 (IL-1) via stress-activated protein kinases (SAPK)/ c-Jun NH-2termial kinase (JNK). A peroxisome proliferator-activated receptor gamma (PPARγ) agonist, pioglitazone hydrochloride attenuated the expression of fibrotic marker such as α-SMA and galectin-3 and collagen1 via SAPK/JNK signaling. Pioglitazone also suppressed DOX-induced early fibrotic response in vivo. In conclusion, these findings suggested that low dose DOX induced reactive fibrotic change of cardiac fibroblasts via cell death-independent pathway. There may be potentially new mechanisms of DOX induced cardiotoxicity in clinical usage.</p>

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