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Delta-opioid receptors (DOR) are involved in cardioprotection under hypoxia/ ischemia. However, the underlying mechanism is not well understood yet. We have recently shown that DOR activation significantly modify the expression of hypoxia-sensitive microRNAs (miRNAs) in the brain and kidney. In extension, we further investigated if DOR activation can regulate cardiac miRNAs in hypoxia. We compared global changes in miRNA gene expression in the rat heart following exposure to hypoxia for 10 days with those in normoxia using a low density miRNA microarray to delineate hypoxia-induced changes in the miRNA expression. The up-regulated miRNAs from the microarray analysis were selected for further investigating their response to hypoxia and DOR activation with a DOR agonist, UFP-512 after 1, 5, and 10 days. We found that 1) miR-376a increased after 1-day hypoxia and progressively increased with hypoxic duration; 2) miR-7b, miR-107, miR-134, miR-135a, miR-193a-3p, miR-196a and miR-324-3p progressively increased after 1-day hypoxia and reached a peak after 5-days; 3) miR-7a, miR-141, miR-196c, miR-200a, miR-200b, miR-203a and miR-324 increased only after 1-day hypoxia and significantly decreased after 5-10 days of hypoxia; 4) miR-128a did not significantly change after 1-10 days of hypoxia. After DOR activation with UFP-512, miR-128a, miR-135a, miR-193a-3p, miR-196a, miR-200a, miR-324-3p and miR-338 continued to increase after 1-day hypoxia, and then decreased after 5-10 days of hypoxia; 5) miR-7b and miR-134, in the condition of DOR activation, increased after 1-day hypoxia and further increased after 5-day hypoxia, while significantly decreased after 10-day exposure. In contrast, some miRNAs like miR-350 decreased in response to hypoxia, while DOR activation almost completely reversed such hypoxic reduction. These results suggest that cardiac miRNAs differentially respond to hypoxic stress with a variable degree directly related to the duration of hypoxic exposure, and DOR activation can regulate such hypoxic responses. Supported by HD034852 , AT004422 , NSFC31071046, CS20102010, ZD201007 , CY 20119004,CY20120003, STCSM10DZ1975800,NBRP09CB522901 & 12CB518502.

Cardiovascular dysfunction often causes blood/oxygen insufficiency in the kidney that is very sensitive to changes in oxygen/blood delivery. Indeed, hypoxic/ischemic kidney stress is a frequent problem in clinical settings. There is, however, no promising strategy for prevention and treatment of such injury. Since recent studies suggest that microRNAs are differentially involved in hypoxic/ischemic events and delta-opioid receptor (DOR) activation increases antioxidant capacity and protects against hypoxic/ischemic injury, we asked if DOR activation regulates microRNA expression in the kidney under hypoxic condition. We isolated microRNAs from normoxic and hypoxic rat kidneys and used the paired microRNAs for microarray analysis. Thirty-one microRNAs were selected for quantitative PCR analysis based on the microarray data. Among them, 14 microRNAs were significantly altered in response to prolonged hypoxia for 1, 5 and 10 days, DOR activation with UFP-512 (1 mg/kg/day, ip, at days 0, 4 and 8) or a combination of both. Our novel data show that 1) DOR activation shifts miRNA expression profiles in normoxic conditions; 2) hypoxia differentially alters the miRNA expression profiles depending on hypoxic durations; and 3) DOR activation modifies hypoxia-induced changes in miRNA expression. For example, 10-day hypoxia reduced the level of miR-212 by >70% (p100% (p