Abstract 14707: Gene Therapy With Calsarcin-1-AAV9 Rescues Contractile Dysfunction In Angiotensin-II Treated Mice
Sustained hemodynamic stress, e.g. due to hypertension or valvular defects, ultimately results in pathological remodeling of the myocardium, characterized by hypertrophy, fibrosis and progressive contractile dysfunction. The phosphatase calcineurin plays a key role in the molecular pathogenesis of these processes. In previous experiments, we could show the mice deficient for the calcineurin-interacting protein calsarcin-1 (CS1) were sensitized to cardiomyopathic stimuli. Conversely, transgenic mice with a cardiac restricted overexpression of CS1 were protected against prohypertophic stimuli. To further explore the therapeutic potential of calsarcin-1, we now generated an adeno-associated virus serotype 9 (CS1-AAV9) expressing CS1 under the control of a cardiac-specific MLC2-CMV promoter. CS1-AAV9 or a control AAV9 encoding for luciferase (Luc-AAV9) were systemically injected into adult male C57Bl/6 mice (2x1011 genomes/mouse). After one week, osmotic minipumps were implanted for another two weeks infusing Ang-II (1000 ng/kg/min) or 0.9% NaCl, respectively. Echocardiography revealed contractile dysfunction in mice treated with control virus with a decrease of the fractional shortening (FS) from 45.4 to 37.5% (n=11–12, p<0.01) upon Ang-II stimulation. In contrast, AAV9-mediated CS1-overexpression completely prevented Ang-II-induced LV-dysfunction (FS=45.3% in AAV9-CS1-Ang-II-mice, p<0,001 vs. AAV9-Luc-Ang-II). Interestingly, the moderate overexpression of CS1 (23%. vs. 140% in the transgenic mice) did not lead to a significant reduction of Ang-II-mediated hypertrophy (7.2 mg/g heart/body weight ratio in AAV9-Ren-Ang-II vs. 7.0 mg/g in AAV9-CS1-Ang-II). In line with the echocardiographic results, the Ang-II-induced “fetal” gene program (including ANF, BNP, and b-MHC) was significantly blunted in AAV-CS1 treated animals. Similarly, the degree of fibrosis was reduced by 51% (p<0.01). Mechanistically, these effects were most likely mediated by the inhibition of calcineurin as shown by reduction of the expression of the calcineurin-responsive gene RCAN1–4 (−55% on protein/ -58% on mRNA level, both p<0.05)Taken together, these results add further evidence that CS1 attenuates pathological cardiac remodeling.
- © 2010 by American Heart Association, Inc.