{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:06:10Z","timestamp":1791295570512,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"16","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2005,10,18]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Angiotensin-converting enzyme (ACE) inhibitors are valuable agents for the treatment of hypertension, heart failure, and other cardiovascular and renal diseases. The cardioprotective effects of ACE inhibitors are mediated by blockade of both conversion of angiotensin (Ang) I to Ang II and kinin hydrolysis. Here, we report a novel mechanism that may explain the cardiac antifibrotic effect of ACE inhibition, involving blockade of the hydrolysis of N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP).\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            To study the role of Ac-SDKP in the therapeutic effects of the ACE inhibitor captopril, we used a model of Ang II\u2013induced hypertension in rats treated with the ACE inhibitor either alone or combined with a blocking monoclonal antibody (mAb) to Ac-SDKP. These hypertensive rats had left ventricular hypertrophy (LVH) as well as increases in cardiac fibrosis, cell proliferation, transforming growth factor-\u03b2 (TGF-\u03b2) expression, and phosphorylation of Smad2 (P-Smad2), a signaling mediator of the effects of TGF-\u03b2. The ACE inhibitor did not decrease either blood pressure or LVH; however, it significantly decreased LV collagen from 13.3\u00b10.9 to 9.6\u00b10.6 \u03bcg\/mg dry wt (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.006), and this effect was blocked by the mAb (12.1\u00b10.6;\n            <jats:italic>P<\/jats:italic>\n            &lt;0.034, ACE inhibitor versus ACE inhibitor+mAb). In addition, analysis of interstitial collagen volume fraction and perivascular collagen (picrosirius red staining) showed a very similar tendency. Likewise, the ACE inhibitor significantly decreased LV monocyte\/macrophage infiltration, cell proliferation, and TGF-\u03b2 expression, and these effects were blocked by the mAb. Ang II increased Smad2 phosphorylation 3.2\u00b10.9-fold; the ACE inhibitor lowered this to 0.6\u00b10.1-fold (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.001), and the mAb blocked this decrease to 2.1\u00b10.3 (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.001, ACE inhibitor versus ACE inhibitor+mAb). Similar findings were seen when the ACE inhibitor was replaced by Ac-SDKP.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            We concluded that in Ang II\u2013induced hypertension, the cardiac antifibrotic effect of ACE inhibitors is a result of the inhibition of Ac-SDKP hydrolysis, resulting in a decrease in cardiac cell proliferation (probably fibroblasts), inflammatory cell infiltration, TGF-\u03b2 expression, Smad2 activation, and collagen deposition.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.104.528695","type":"journal-article","created":{"date-parts":[[2005,10,11]],"date-time":"2005-10-11T00:33:20Z","timestamp":1128990800000},"page":"2436-2445","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":140,"title":["Angiotensin-Converting Enzyme Inhibitors"],"prefix":"10.1161","volume":"112","author":[{"given":"Hongmei","family":"Peng","sequence":"first","affiliation":[{"name":"From the Hypertension and Vascular Research Division (H.P., O.A.C., N.V., T.-D.L., A.M., N.-E.R.) and the Biostatistics and Research Epidemiology Division (E.L.P.), Henry Ford Hospital, Detroit, Mich."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar A.","family":"Carretero","sequence":"additional","affiliation":[{"name":"From the Hypertension and Vascular Research Division (H.P., O.A.C., N.V., T.-D.L., A.M., N.-E.R.) and the Biostatistics and Research Epidemiology Division (E.L.P.), Henry Ford Hospital, Detroit, Mich."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikola","family":"Vuljaj","sequence":"additional","affiliation":[{"name":"From the Hypertension and Vascular Research Division (H.P., O.A.C., N.V., T.-D.L., A.M., N.-E.R.) and the Biostatistics and Research Epidemiology Division (E.L.P.), Henry Ford Hospital, Detroit, Mich."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tang-Dong","family":"Liao","sequence":"additional","affiliation":[{"name":"From the Hypertension and Vascular Research Division (H.P., O.A.C., N.V., T.-D.L., A.M., N.-E.R.) and the Biostatistics and Research Epidemiology Division (E.L.P.), Henry Ford Hospital, Detroit, Mich."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Apurva","family":"Motivala","sequence":"additional","affiliation":[{"name":"From the Hypertension and Vascular Research Division (H.P., O.A.C., N.V., T.-D.L., A.M., N.-E.R.) and the Biostatistics and Research Epidemiology Division (E.L.P.), Henry Ford Hospital, Detroit, Mich."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward L.","family":"Peterson","sequence":"additional","affiliation":[{"name":"From the Hypertension and Vascular Research Division (H.P., O.A.C., N.V., T.-D.L., A.M., N.-E.R.) and the Biostatistics and Research Epidemiology Division (E.L.P.), Henry Ford Hospital, Detroit, Mich."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nour-Eddine","family":"Rhaleb","sequence":"additional","affiliation":[{"name":"From the Hypertension and Vascular Research Division (H.P., O.A.C., N.V., T.-D.L., A.M., N.-E.R.) and the Biostatistics and Research Epidemiology Division (E.L.P.), Henry Ford Hospital, Detroit, Mich."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.96.11.4002"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.3.779"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V82.11.3307.3307"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI118484"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.30.5.1015"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.37.3.827"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.hyp.0000025880.56816.fa"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/circ.103.25.3136"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1161\/hyp.37.2.794"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.1997.0435"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1006\/jmcc.2000.1215"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.cir.0000020689.12472.e0"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/370341a0"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.biochem.67.1.753"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1161\/res.74.4.8137508"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1097\/00004872-200403000-00023"},{"key":"e_1_3_2_17_2","first-page":"325","volume":"147","year":"1995","unstructured":"Cleutjens JP, Verluyten MJ, Smiths JF, Daemen MJ. 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