Ac‐SDKP prevents cardiac fibrosis and dysfunction induced by galectin‐3, role of TGF‐β/Smad3 signaling pathway

Abstract

We hypothesized that Ac‐SDKP (N‐Acetyl‐Seryl‐Aspartyl‐Lysyl‐Proline) prevents galectin‐3 (Gal‐3) induced cardiac inflammation, fibrosis and dysfunction, and these effects are mediated by the TGF‐ β/Smad3 signaling pathway. We infused Gal‐3 or/and Ac‐SDKP intrapericardially. Adult male Spregue Dawley rats received the following treatment for 4 weeks: vehicle, Ac‐SDKP (800 µg/kg/day), Gal‐3 (0.5 µg/hr), and Ac‐SDKP + Gal‐3. Hemodynamics, left ventricular ejection fraction (LVEF) and transmitral velocity were measured by echocardiography; inflammation and collagen deposition in the heart by histological and immunohistochemical staining and TGF‐β expression and Smad3 activation (p‐Smad3) by Western blot. We found 1) Gal‐3 enhanced macrophage and mast cell infiltration, increased cardiac interstitial and perivascular fibrosis; decreased ‐dP/dt response to isoproterenol challenge, E/A ratio and LVEF. 2) Ac‐SDKP prevented these adverse effects; 3) Gal‐3 increased TGF‐β expression by 3.94 fold (p < 0.01, Gal‐3 vs vehicle) and Smad3 phosphorylation 5.66 fold (p < 0.05, Gal‐3 vs vehicle) in LV; Ac‐SDKP reduced TGF‐β to 1.2 fold (p < 0.05); p‐Smad to 1.3 fold (p = 0.052), Gal‐3 + Ac‐SDKP vs Gal‐3). We conclude that Ac‐SDKP prevents Gal‐3 induced cardiac inflammation, fibrosis and dysfunction possibly via inhibition of the TGF‐β /Smad3 signaling pathway.