{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:47:24Z","timestamp":1789753644653,"version":"4.0.1"},"reference-count":49,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2024,2,6]]},"abstract":"<jats:sec sec-type=\"background\" xml:lang=\"en\">\n            <jats:title>Background<\/jats:title>\n            <jats:p xml:lang=\"en\">Small conductance calcium\u2010activated potassium (SK) channels are largely responsible for endothelium\u2010dependent coronary arteriolar relaxation. Endothelial SK channels are downregulated by the reduced form of nicotinamide adenine dinucleotide (NADH), which is increased in the setting of diabetes, yet the mechanisms of these changes are unclear. PKC (protein kinase C) is an important mediator of diabetes\u2010induced coronary endothelial dysfunction. Thus, we aimed to determine whether NADH signaling downregulates endothelial SK channel function via PKC.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Methods and Results<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              SK channel currents of human coronary artery endothelial cells were measured by whole cell patch clamp method in the presence\/absence of NADH, PKC activator phorbol 12\u2010myristate 13\u2010acetate, PKC inhibitors, or endothelial PKC\n              <jats:sub>\u03b1<\/jats:sub>\n              \/PKC\n              <jats:sub>\u03b2<\/jats:sub>\n              knockdown by using small interfering RNA. Human coronary arteriolar reactivity in response to the selective SK activator NS309 was measured by vessel myography in the presence of NADH and PKC\n              <jats:sub>\u03b2<\/jats:sub>\n              inhibitor LY333531. NADH (30\u2013300\u2009\u03bcmol\/L) or PKC activator phorbol 12\u2010myristate 13\u2010acetate (30\u2013300\u2009nmol\/L) reduced endothelial SK current density, whereas the selective PKC\n              <jats:sub>\u1d66<\/jats:sub>\n              inhibitor LY333531 significantly reversed the NADH\u2010induced SK channel inhibition. PKC\n              <jats:sub>\u03b2<\/jats:sub>\n              small interfering RNA, but not PKC\n              <jats:sub>\u03b1<\/jats:sub>\n              small interfering RNA, significantly prevented the NADH\u2010 and phorbol 12\u2010myristate 13\u2010acetate\u2013induced SK inhibition. Incubation of human coronary artery endothelial cells with NADH significantly increased endothelial PKC activity and PKC\n              <jats:sub>\u03b2<\/jats:sub>\n              expression and activation. Treating vessels with NADH decreased coronary arteriolar relaxation in response to the selective SK activator NS309, and this inhibitive effect was blocked by coadministration with PKC\n              <jats:sub>\u03b2<\/jats:sub>\n              inhibitor LY333531.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec xml:lang=\"en\">\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p xml:lang=\"en\">\n              NADH\u2010induced inhibition of endothelial SK channel function is mediated via PKC\n              <jats:sub>\u03b2<\/jats:sub>\n              . These findings may provide insight into novel therapeutic strategies to preserve coronary microvascular function in patients with metabolic syndrome and coronary disease.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/jaha.123.031028","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T11:15:18Z","timestamp":1706699718000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":12,"title":["Role of Protein Kinase C in Metabolic Regulation of Coronary Endothelial Small Conductance Calcium\u2010Activated Potassium Channels"],"prefix":"10.1161","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5634-1037","authenticated-orcid":false,"given":"Hang","family":"Xing","sequence":"first","affiliation":[{"name":"Division of Cardiothoracic Surgery, Rhode Island Hospital Alpert Medical School of Brown University Providence RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8169-6753","authenticated-orcid":false,"given":"Sharif A.","family":"Sabe","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, Rhode Island Hospital Alpert Medical School of Brown University Providence RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangbin","family":"Shi","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, Rhode Island Hospital Alpert Medical School of Brown University Providence RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dwight D.","family":"Harris","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, Rhode Island Hospital Alpert Medical School of Brown University Providence RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhong","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, Rhode Island Hospital Alpert Medical School of Brown University Providence RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8886-801X","authenticated-orcid":false,"given":"Frank W.","family":"Sellke","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, Rhode Island Hospital Alpert Medical School of Brown University Providence RI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4762-7532","authenticated-orcid":false,"given":"Jun","family":"Feng","sequence":"additional","affiliation":[{"name":"Division of Cardiothoracic Surgery, Rhode Island Hospital Alpert Medical School of Brown University Providence RI"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.5339\/gcsp.2014.43"},{"key":"e_1_3_2_3_2","first-page":"853","article-title":"Endothelial dysfunction in diabetes mellitus","volume":"3","author":"Hadi HA","year":"2007","unstructured":"Hadi HA, Suwaidi JA. 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