Abstract 15878: GSK-3α in Fibroblasts Attenuates Cardiac Fibrosis and Dysfunction Induced by Pressure Overload Through Modulation of TGFβ1
Glycogen synthase kinase-3α (GSK-3α) is a ubiquitously expressed S/T kinase that has versatile functions. Cardiac-specific loss of GSK-3α has outcomes that contrast with those of systemic deletion of GSK-3α after myocardial infarction, indicating cell type-specific roles of GSK-3α. However, the role of GSK-3α in fibroblasts (FB) remains to be defined. We hypothesized that GSK-3α in FB attenuates cardiac fibrosis (CF) and dysfunction in response to pressure overload (PO), and subjected FB-specific GSK-3α knockout mice (GSK-3αf/f/FSP-Cre, KO) and littermate GSK-3αf/f mice (CT) to 4 weeks of PO induced by transverse aortic constriction. The CF (%) was greater in KO than in CT (1.9±0.2 vs 1.1±0.1, p<0.01) after sham operation, showing that loss of GSK-3α in FB causes CF at baseline. After PO, CF was increased in both KO and CT, and there was much more in KO than in CT (7.9±1.3 vs 3.8±0.4, p<0.01). There was significantly more type I and type III collagen in KO than in CT after PO. Cardiac FB (%) measured by positive HSP47 staining area was more in KO than in CT after PO (22±1 vs 11±1, p<0.005). These data suggest that loss of GSK-3α in FB promotes CF. The lung weight/body weight (mg/g) was greater in KO than in CT (11.3±1.8 vs 7.7±0.7, p<0.05) after PO, indicating that KO had more severe lung congestion. Left ventricular (LV) ejection fraction (EF) and fractional shortening (FS) were not significantly different between sham KO and CT. The EF (45±5% vs 58±3%, p<0.05) and FS (19±2% vs 25±2%, p<0.05) were lower in KO than in CT after PO. LV ±dP/dts (mmHg/s) were lower in KO than in CT after PO (+dP/dt, 5306±358 vs 7536±541, p<0.01; -dP/dt, 6250±404 vs 8893±353, p<0.001) although they were not significantly different between sham KO and CT. LV end-diastolic pressure was higher in KO than in CT (15±2 vs 9±2, p<0.05) after PO. These data show that loss of GSK-3α in FB exacerbates PO-induced cardiac dysfunction. More TGFβ1 was observed in cardiac FB in KO than in CT after PO. In neonatal rat cardiac FB, knockdown of GSK-3α increased the levels of TGFβ1, phospho-Smad3, α-smooth muscle actin, and Ki67-positive cells, showing that GSK-3α inhibits proliferation and myofibroblast transformation of FB. In conclusion, GSK-3α in FB protects against PO-induced CF and dysfunction through inhibition of TGFβ1.
Author Disclosures: P. Zhai: None. A. Shirakabe: None. B. Magrys: None. J. Sadoshima: None.
- © 2015 by American Heart Association, Inc.