Natriuretic Peptide Receptor 3 (NPR3), the clearance receptor for extracellular bio-active natriuretic peptides (NPs), plays important roles in the homeostasis of body fluid volume and vascular tone. Using luciferase reporter and antagomir-based silencing assays, we demonstrated that the expression of NPR3 could be modulated by microRNA-143 (miR-143-3p), a microRNA species with up-regulated circulating concentrations in clinical heart failure. The regulatory effect of miR-143 on NPR3 expression was further evidenced by the reciprocal relationship between miR-143 and NPR3 levels observed in hypoxia-treated human cardiac cells and in left ventricular tissue from rats undergoing experimental myocardial infarction. Further analysis indicated elevation of miR-143 in response to hypoxic challenge reflects transcriptional activation of the miR-143 host gene (MIR143HG). This was corroborated by demonstration of the induction of host gene promoter activity upon hypoxic challenge. Moreover, miR-143 was shown to enhance its own expression by increasing MIR143HG promoter activity, as well as targeting the expressions of NPPA, NPPC, NR3C2, and CRHR2 in cardiac cells. Taken together, these findings suggest that the elevation of miR-143 upon hypoxic insult may be part of a microRNA-based feed forward loop that results in fine tuning the levels of NPs and neurohormonal receptors in cardiac cell lineages.