Background: XBP1 is a key transcription factor of the unfolded protein response in mammalian cells, which is involved in several cardiovascular pathological progression including cardiac hypertrophy and myocardial infarction, but its expression trend, function and upstream regulate mechanism in the development of heart failure are unclear. In the present study, therefore, the potential role of miRNAs in the regulation of XBP1 expression in heart failure was examined. Methods and results: First, western blots showed that cardiac expression of ER stress marker XBP1 were induced in the early adaptive phase, but decreased in the maladaptive phase in hypertrophic and failing heart, while there was no obvious change of upstream ATF6 and IRE1 activity in this progression. Interestingly, we further found that XBP1 and its downstream target VEGF were attenuated by miR-30* and miR-214 in cardiomyocyte. Moreover, we found that miR-30* was significantly reduced in the early phase of cardiac hypertrophic animal model and in human failing hearts, while both miR-214 and miR-30* were increased in the maladaptive diseased heart, thereby contribute to impairment of cardiac XBP1 and VEGF expression. Conclusions: These results provide the first clear link between miRNAs and direct regulation of XBP1 in heart failure and reveal that miR-214 and miR-30* synergistically regulates cardiac VEGF expression and angiogenesis by targeting XBP1 in the progression from adaptive hypertrophy to heart failure.