Cardiac-targeted RNA Interference Against STIM1 Using a Recombinant AAV9 Vector Limits the Progression of Heart Failure in Rats

초록

Background: Activation of the calcineurin/NFAT signaling pathway promotes pathological remodeling of the heart. Stromal interaction molecule 1 (STIM1), a transmembrane endoplasmic reticulum calcium sensor expressed in cardiomyocytes, has recently been identified as a potent positive regulator of NFAT. We thus hypothesized that STIM1 silencing will limit the progression of heart failure (HF). Methods and results: To deliver RNA interference in a rat model of heart failure, dimeric cardiotropic adeno-associated vectors encoding for a short hairpin RNA against STIM1 or control from a U6 promoter (rAAV9-shSTIM1 or rAAV9-shscrambled) were constructed. rAAV9-shSTIM1 was shown to efficiently silence STIM1 expression in vitro and in vivo without modification of cardiac function or morphology under basal conditions. Trans-aortic banding was performed in 6-weeks old Sprague Dawley rats that led to HF development in 20 to 30 weeks. Rats were then randomized to receive rAAV9-shSTIM1 (n=4) or rAAV9-shScrambled (n=3) by tail vein injection (5×10e11 viral genomes). Two months after injection, echocardiographic assessment of ventricular function showed a significant improvement in the group treated with rAAV9-shSTIM1 therapy compared to the control group (figure 1, p<0.01). Compared to rAAV9-shScrambled-treated rats, rAAV9-shSTIM1 therapy tends to improve cardiac dilation (left ventricular diastolic diameter: 8.2±0.9 versus 7.4±0.6 mm, p=0.07). Conclusion: A novel cardiotropic AAV9 short hairpin RNA vector silences STIM1 in cardiomyocytes and improves cardiac function in pressure-overload induced heart failure rats.