Introduction:
Cardiac hypertrophy is an adaptive response to increased physiologic or pathologic hemodynamic stress. Previous work from our laboratory suggested that the CEBPβ/ CITED4 pathway plays an important role in exercise-induced cardiac hypertrophy. Consistent with this model, our laboratory recently found that inducible cardiac expression of CITED4 in adult mice increases in heart weight and cardiomyocyte size with normal systolic function and a gene expression profile consistent with physiologic growth. After ischemia-reperfusion injury (IRI), induced CITED4 mice show significant functional recovery and evidence for decreased adverse remodeling.
Hypothesis:
Here, we assessed the hypothesis that CITED4 gene therapy delivered in a clinically relevant time frame after IRI in a mouse model, will also lead to improved systolic function and favorable cardiac remodeling.
Methods and Results:
Cardiomyocyte-specific CITED4 gene delivery via intravenous AAV9 (CITED4 and GFP control) injections in young wild type (WT) mice led to a steady 4-fold increase in cardiac CITED4 expression. After four weeks, CITED4 treated animals developed physiologic cardiac hypertrophy with increased heart weights (heart weight to tibia length controls 6.54±0.17g/mm vs. CITED4 7.31±0.12g/mm), as well as increased left ventricular mass index and wall thickness with unchanged systolic function evaluated by echocardiography. CITED4 gene therapy in the setting of IRI, delivered 20min. after reperfusion, promoted decreased maladaptive remodeling with improved systolic function (%FS controls 37.5±3.6 vs. C4KO 47.9±1.6), a smaller scar size (% fibrotic area controls 9.1±1.9 vs. C4KO 2.4±0.5) and a favorable gene expression profile eight weeks after IRI. After injury, CITED4 gene therapy led to a 6-fold overexpression already after one week post-IRI, responsible for less apoptosis, fibrosis and inflammation when compared to control mice.
Conclusion:
Taken together, our data identify CITED4 as a regulator of physiologic cardiac growth that protects against adverse remodeling after ischemic injury in a clinically relevant therapeutic intervention after IRI. CITED4 may represent a novel therapeutic target to mitigate adverse ventricular remodeling.
The cardioprotective efficacy of
TVP
1022 against ischemia/reperfusion injury and cardiac remodeling in rats