Abstract 271: A Novel Functional Role for Plasma miR-30d in Dyssynchronous Heart Failure
Introduction: We have previously shown that plasma miR-30d level is an independent predictor of echocardiographic response to cardiac resynchronization therapy (CRT) in patients with dyssynchronous heart failure (DHF). We now test the hypothesis that miR-30d is dynamically regulated in cardiomyocytes (CMs) and plays a functional role in DHF.
Methods: miR-30d levels were assessed in a canine model of DHF and CRT using qRT-PCR, and potential miR-30d targets were identified using a bioinformatics approach. miR-30d targets were validated in the canine model and in CMs in culture. The regulation and functional role of miR-30d was investigated in CMs in culture using microscopy, western blotting and qRT-pCR.
Results: miR-30d is enriched in the coronary sinus compared to peripheral blood in human patients, suggesting a cardiac origin (n=7, p<0.05). In tissue samples from the canine model of DHF, miR-30d levels are highest in the lateral wall, in concert with the greatest wall stress, and decreases with CRT (n=5, p<0.05). Bioinformatics analysis using differential gene expression data and in silico miR target prediction algorithms identified integrin and PI3/Akt signaling pathways as targets of miR-30d. Several targets including MAP4K4 and lims1 were further validated in tissue as well as in cultured CMs (n=4, p<0.05). miR-30d appears to be expressed in CMs, packaged into exosomes and micovesicles, and released in response to pathological rotational stress (n=2). Over-expression of miR-30d in CMs induces cellular hypertrophy with a unique expression signature of cardiac hypertrophy markers most consistent with physiological hypertrophy (n=3, p<0.05). Overexpression of miR-30d appears to be cardioprotective by abrogating TNF-induced increase in MAP4K4 expression (n=4, p<0.05).
Conclusions: miR-30d is dynamically regulated in DHF and appears to play an important role in CM biology. Further insight into the role of ‘stretch’-regulated microRNAs such as miR-30d may pave the way for novel therapeutic and diagnostic strategies.
- © 2013 by American Heart Association, Inc.