Abstract 18184: Deficiency in the Novel Small Leucin-Rich Repeat Protein Podocan Promotes Pressure Load-Induced Cardiac Hypertrophy
Background: Extracellular matrix (ECM) molecules have been increasingly implicated in cardiac remodeling, and in particular the myocardial response to pressure overload. Podocan is a novel member of the small leucin-rich-repeat protein family of ECM proteins. We recently have characterized podocan as an inhibitor of the migration and proliferation of vascular smooth muscle cells. Now we are testing if podocan deficiency has an effect on pressure load-induced cardiac hypertrophy.
Methods and Results: We induced pressure overload cardiac hypertrophy using aortic banding (AB) in mice (age 10-12 weeks) with podocan-/- (n=6) and wild-type (WT) (n=7) genotype. Four weeks after AB, cardiac anatomy and function were assessed by echocardiography. In addition, histological analysis was used to assess the myocardial response to AB. Podocan-deficient mice showed significantly greater cardiac hypertrophy compared with WT mice after AB, whereas no significant differences were observed when comparing sham-operated animals. Heart to body weight ratio was 6±1 mg/g in WT-mice versus 10±2 mg/g with podocan-/- genotype (P<0.05). The expression of podocan and non-phospho-beta catenin (NPBC), an indicator of canonical Wnt-pathway activation, were evaluated by immunohistochemistry in serial myocardial cross-sections (n=12 per animal) (data as mean % cells±SEM). Four weeks after AB, myocardium from mice with WT-genotype exhibited abundant podocan expression both extra-cellular as well as intra-cellular. Podocan expression was also seen in areas surrounding micro-vessels. As expected, podocan was absent in myocardium from podocan-/- mice. Of note, the nuclear expression of NPBC was strongly increased in podocan-/- myocardium compared with WT (34±7% vs. 11±2%, P<0.05). Immunofluorescence double labeling showed colocalization of troponin-I and NPBC in hypertrophic myocardium with podocan-/- genotype.
Conclusions: Deficiency in podocan promotes cardiac hypertrophy in response to pressure overload. Greater hypertrophy seen in the absence of podocan was associated with evidence of increased Wnt-pathway activation. This first report of the role of podocan in pressure overload identifies it as a novel and important regulator of myocardial remodeling.
- © 2013 by American Heart Association, Inc.