Activation of Delta-Opioid Receptors Regulates Cardiac MicroRNA Expression Under Hypoxia

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.