{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T07:19:48Z","timestamp":1792739988775,"version":"4.5.0"},"reference-count":69,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation Research"],"published-print":{"date-parts":[[1999,3,19]]},"abstract":"<jats:p>\n            <jats:italic>Abstract<\/jats:italic>\n            \u2014Although isoform-selective translocation of protein kinase C (PKC) \u03b5 appears to play an important role in the late phase of ischemic preconditioning (PC), the mechanism(s) responsible for such translocation remains unclear. Furthermore, the signaling pathway that leads to the development of late PC after exogenous administration of NO in the absence of ischemia (NO donor\u2013induced late PC) is unknown. In the present study we tested the hypothesis that NO activates PKC and that this is the mechanism for the development of both ischemia-induced and NO donor\u2013induced late PC. A total of 95 chronically instrumented, conscious rabbits were used. In rabbits subjected to ischemic PC (six 4-minute occlusion\/4-minute reperfusion cycles), administration of the NO synthase inhibitor\n            <jats:italic>N<\/jats:italic>\n            <jats:sup>\u03c9<\/jats:sup>\n            -nitro-\n            <jats:sc>l<\/jats:sc>\n            -arginine (group III), at doses previously shown to block the development of late PC, completely blocked the ischemic PC\u2013induced translocation of PKC\u03b5 but not of PKC\u03b7, indicating that increased formation of NO is an essential mechanism whereby brief ischemia activates the \u03b5 isoform of PKC. Conversely, a translocation of PKC\u03b5 and -\u03b7 quantitatively similar to that induced by ischemic PC could be reproduced pharmacologically with the administration of 2 structurally unrelated NO donors, diethylenetriamine\/NO (DETA\/NO) and\n            <jats:italic>S<\/jats:italic>\n            -nitroso-\n            <jats:italic>N<\/jats:italic>\n            -acetylpenicillamine (SNAP), at doses previously shown to elicit a late PC effect. The particulate fraction of PKC\u03b5 increased from 35\u00b12% of total in the control group (group I) to 60\u00b11% after ischemic PC (group II) (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05), to 54\u00b12% after SNAP (group IV) (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05) and to 52\u00b12% after DETA\/NO (group V) (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05). The particulate fraction of PKC\u03b7 rose from 66\u00b15% in the control group to 86\u00b13% after ischemic PC (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05), to 88\u00b12% after SNAP (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05) and to 85\u00b11% after DETA\/NO (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05). Neither ischemic PC nor NO donors had any appreciable effect on the subcellular distribution of PKC\u03b1, -\u03b21, -\u03b22, -\u03b3, -\u03b4, -\u03bc, or -\u03b9\/\u03bb; on total PKC activity; or on the subcellular distribution of total PKC activity. Thus, the effects of SNAP and DETA\/NO on PKC closely resembled those of ischemic PC. The DETA\/NO\u2013induced translocation of PKC\u03b5 (but not that of PKC\u03b7) was completely prevented by the administration of the PKC inhibitor chelerythrine at a dose of 5 mg\/kg (group VI) (particulate fraction of PKC\u03b5, 38\u00b14% of total,\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05 versus group V; particulate fraction of PKC\u03b7, 79\u00b12% of total). The same dose of chelerythrine completely prevented the DETA\/NO\u2013induced late PC effect against both myocardial stunning (groups VII through X) and myocardial infarction (groups XI through XV), indicating that NO donors induce late PC by activating PKC and that among the 10 isozymes of PKC expressed in the rabbit heart, the \u03b5 isotype is specifically involved in the development of this form of pharmacological PC. In all groups examined (groups I through VI), the changes in the subcellular distribution of PKC\u03b5 protein were associated with parallel changes in PKC\u03b5 isoform\u2013selective activity, whereas total PKC activity was not significantly altered. Taken together, the results provide direct evidence that isoform-selective activation of PKC\u03b5 is a critical step in the signaling pathway whereby NO initiates the development of a late PC effect both after an ischemic stimulus (endogenous NO) and after treatment with NO-releasing agents (exogenous NO). To our knowledge, this is also the first report that NO can activate PKC in the heart. The finding that NO can promote isoform-specific activation of PKC identifies a new biological function of this radical and a new mechanism in the signaling cascade of ischemic PC and may also have important implications for other pathophysiological conditions in which NO is involved and for nitrate therapy.\n          <\/jats:p>","DOI":"10.1161\/01.res.84.5.587","type":"journal-article","created":{"date-parts":[[2012,6,12]],"date-time":"2012-06-12T00:47:05Z","timestamp":1339462025000},"page":"587-604","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":199,"title":["Isoform-Selective Activation of Protein Kinase C by Nitric Oxide in the Heart of Conscious Rabbits"],"prefix":"10.1161","volume":"84","author":[{"given":"Peipei","family":"Ping","sequence":"first","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hitoshi","family":"Takano","sequence":"additional","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Zhang","sequence":"additional","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xian-Liang","family":"Tang","sequence":"additional","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumin","family":"Qiu","sequence":"additional","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard C. X.","family":"Li","sequence":"additional","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Supratim","family":"Banerjee","sequence":"additional","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Buddhadeb","family":"Dawn","sequence":"additional","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zarema","family":"Balafonova","sequence":"additional","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Bolli","sequence":"additional","affiliation":[{"name":"From the Experimental Research Laboratory (P.P., H.T., J.Z., X-L.T., Y.Q., R.C.X.L., S.B., B.D., Z.B., R.B), Division of Cardiology, and the Department of Physiology and Biophysics (P.P., Z.B., R.B.), University of Louisville, and Jewish Hospital Heart and Lung Institute, Louisville, Ky."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.72.6.8495557"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.88.3.1264"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI117667"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118449"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.79.3.424"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.1995.tb15866.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1997.273.4.C1324"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.81.1.42"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.81.6.1094"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.1997.273.6.H2931"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.98.5.441"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1996.tb33510.x"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00795364"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.83.1.73"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1994.tb36719.x"},{"key":"e_1_3_2_16_2","first-page":"137","volume":"3","year":"1995","unstructured":"Cohen MV, Downey JM. 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