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1 Pharmacology, University of California, San Diego, La Jolla, CA, USA; Anesthesiology, University of California, San Diego, La Jolla, CA, USA
2 Pharmacology, University of California, San Diego, La Jolla, CA, USA
3 Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA
4 Anesthesiology, University of California, San Diego, La Jolla, CA, USA; Anesthesiology, VA San Diego Healthcare Systems, San Diego, CA, USA
5 Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA
6 Pharmacology, University of California, San Diego, La Jolla, CA, USA; Medicine, University of California, San Diego, La Jolla, CA, USA
* To whom correspondence should be addressed. E-mail: hepatel{at}ucsd.edu.
The role of caveolae, membrane microenvironments enriched in signaling molecules, in myocardial ischemia is poorly defined. In the current study, we used cardiac myocytes prepared from adult rats to test the hypothesis that opioid receptors (OR), which are capable of producing cardiac protection in vivo, promote cardiac protection in cardiac myocytes in a caveolae-dependent manner. We determined protein expression and localization of delta OR (DOR) using co-immunohistochemistry, caveolar fractionation, and immunoprecipitations. DOR co-localized in fractions with caveolin-3 (cav-3), a structural component of caveolae in muscle cells and could be immunoprecipitated by a cav-3 antibody. Immunohistochemistry confirmed plasma membrane co-localization of DOR with cav-3. Cardiac myocytes were subjected to simulated ischemia (2hr) or an ischemic preconditioning (IPC) protocol (10min ischemia; 30min recovery; 2hr ischemia) in the presence and absence of methyl-
-cyclodextrin (MCD, 2mM), which binds cholesterol and disrupts caveolae. We also assessed the cardiac protective effects of SNC-121 (SNC), a selective delta-OR (DOR) agonist, on cardiac myocytes ± MCD and MCD preloaded with cholesterol. Ischemia, simulated by mineral oil layering to inhibit gas exchange, promoted cardiac myocytes cell death (trypan blue staining), a response blunted by SNC (37±3 vs. 59±3 % dead cells in the presence and absence of 1µM SNC, p<0.01) or by use of the IPC protocol (35±4 vs. 62±3 % dead cells, p<0.01). MCD treatment, which disrupted caveolae (as detected by electron microscopy), fully attenuated the protective effects of IPC or SNC, resulting in cell death comparable to that of the ischemic group. By contrast, SNC-induced protection was not abrogated in cells incubated with cholesterol-saturated MCD, which maintained caveolae structure and function. These findings suggest a key role for caveolae, perhaps through enrichment of signaling molecules, in contributing to protection of cardiac myocytes from ischemic damage.
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