{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,8]],"date-time":"2026-11-08T10:38:51Z","timestamp":1794134331790,"version":"4.8.0"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"18","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2008,5,6]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Mice lacking guanylyl cyclase-A (GC-A), a natriuretic peptide receptor, have pressure-independent cardiac hypertrophy. However, the mechanism underlying GC-A\u2013mediated inhibition of cardiac hypertrophy remains to be elucidated. In the present report, we examined the role of regulator of G-protein signaling subtype 4 (RGS4), a GTPase activating protein for G\n            <jats:sub>q<\/jats:sub>\n            and G\n            <jats:sub>i<\/jats:sub>\n            , in the antihypertrophic effects of GC-A.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            In cultured cardiac myocytes, treatment of atrial natriuretic peptide stimulated the binding of guanosine 3\u2032,5\u2032-cyclic monophosphate-dependent protein kinase (PKG) I-\u03b1 to RGS4, PKG-dependent phosphorylation of RGS4, and association of RGS4 and G\u03b1\n            <jats:sub>q<\/jats:sub>\n            . In contrast, blockade of GC-A by an antagonist, HS-142-1, attenuated the phosphorylation of RGS4 and association of RGS4 and G\u03b1\n            <jats:sub>q<\/jats:sub>\n            . Moreover, overexpressing a dominant negative form of RGS4 diminished the inhibitory effects of atrial natriuretic peptide on endothelin-1\u2013stimulated inositol 1,4,5-triphosphate production, [\n            <jats:sup>3<\/jats:sup>\n            H]leucine incorporation, and atrial natriuretic peptide gene expression. Furthermore, expression and phosphorylation of RGS4 were significantly reduced in the hearts of GC-A knockout (GC-A-KO) mice compared with wild-type mice. For further investigation, we constructed cardiomyocyte-specific RGS4 transgenic mice and crossbred them with GC-A-KO mice. The cardiac RGS4 overexpression in GC-A-KO mice significantly reduced the ratio of heart to body weight (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.001), cardiomyocyte size (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.01), and ventricular calcineurin activity (\n            <jats:italic>P<\/jats:italic>\n            &lt;0.05) to 80%, 76%, and 67% of nontransgenic GC-A-KO mice, respectively. It also significantly suppressed the augmented cardiac expression of hypertrophy-related genes in GC-A-KO mice.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            These results provide evidence that GC-A activates cardiac RGS4, which attenuates G\u03b1\n            <jats:sub>q<\/jats:sub>\n            and its downstream hypertrophic signaling, and that RGS4 plays important roles in GC-A\u2013mediated inhibition of cardiac hypertrophy.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.107.732990","type":"journal-article","created":{"date-parts":[[2008,4,29]],"date-time":"2008-04-29T01:24:40Z","timestamp":1209432280000},"page":"2329-2339","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":95,"title":["Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart"],"prefix":"10.1161","volume":"117","author":[{"given":"Takeshi","family":"Tokudome","sequence":"first","affiliation":[{"name":"From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan (K.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Kishimoto","sequence":"additional","affiliation":[{"name":"From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan (K.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takeshi","family":"Horio","sequence":"additional","affiliation":[{"name":"From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan (K.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuji","family":"Arai","sequence":"additional","affiliation":[{"name":"From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan (K.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daryl O.","family":"Schwenke","sequence":"additional","affiliation":[{"name":"From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan (K.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hino","sequence":"additional","affiliation":[{"name":"From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan (K.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ichiro","family":"Okano","sequence":"additional","affiliation":[{"name":"From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan (K.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhei","family":"Kawano","sequence":"additional","affiliation":[{"name":"From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan (K.N.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masakazu","family":"Kohno","sequence":"additional","affiliation":[{"name":"From the Research Institute (T.T., Y.A., D.O.S., J.H., I.O., M.M., K.K.) and Department of Medicine (I.K., T.H., Y.K.), National Cardiovascular Center, Suita, Osaka, Japan; Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University Faculty of Medicine, Kagawa, Japan (M.K.); and Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Kyoto, Japan 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