Abstract 18518: Impaired Cardiac Function and Heart Failure in Transgenic Mice With Cardiac Specific Overexpression of Hasf, a Novel Stem Cell Paracrine Factor
Introduction: We have recently discovered a novel mesenchymal stem cell paracrine factor, named Hypoxia regulated Akt mediated Stem cell Factor (HASF), which confers cardiomyocyte protection from apoptosis via the selective activation of PKC? and inhibition of mitochondrial apoptotic pathways. In this study we generated cardiac specific HASF transgenic mice and studied the effects of its constitutive overexpression in the heart.
Methods and Results: Transgenic HASF mouse lines were generated in which human HASF gene expression is driven under the control of α-MHC promoter. Cardiac specific HASF transgenic mice exhibited impaired cardiac function detected as early as 4 weeks of age (58±1.5 % FS in Wt vs. 50±3.4% and 29.4±5.1% in Tg at 4 and 16 weeks respectively, P<0.05). Despite elevated expression of ANF, BNP and β-MHC, functional impairment was not accompanied by significant hypertrophy or changes in LV mass at this age. However, morphologic analysis of the heart from older mice using H/E and Masson's Trichrome staining showed characteristics typical of hypertrophy and heart failure such as increased cardiomyocyte size and significant cardiomyocyte degeneration. LV mass was also significantly increased in older mice (33%, P<0.05). HASF transgenics showed signs of pulmonary edema and cardiac dilatation with increased mortality within 5–6 month. To gain more insight into the primary pathophysiology, we further studied neonatal cardiomyocytes from transgenic animals. These cells exhibited abnormal calcium oscillation as indicated by Fura analysis. In addition, electron microscopy revealed enlarged mitochondria with partial structural change such swelling and loss of cristae in the cardiomyocytes.
Conclusion: In conclusion, cardiac specific overexpression of HASF resulted in cardiac systolic impairment that seemed to precede detectable cardiac hypertrophy and heart failure. Interestingly, this phenotype is similar to that reported previously for the cardiac specific overxpressing PKCε transgenic mouse. Based on our findings we hypothesize that HASF has a short term effect in promoting cardiomyocyte survival but prolonged expression leads to the development of cardiac remodeling and failure, and that these effects may be mediated by PKCε.
- © 2010 by American Heart Association, Inc.