{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T18:58:19Z","timestamp":1791917899844,"version":"4.3.4"},"reference-count":42,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"2","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2020,7,14]]},"abstract":"<jats:sec>\n            <jats:title>Background:<\/jats:title>\n            <jats:p>\n              High blood pressure is the primary risk factor for cardiovascular death worldwide. Autosomal dominant hypertension with brachydactyly clinically resembles salt-resistant essential hypertension and causes death by stroke before 50 years of age. We recently implicated the gene encoding phosphodiesterase 3A (\n              <jats:italic>PDE3A<\/jats:italic>\n              ); however, in vivo modeling of the genetic defect and thus showing an involvement of mutant PDE3A is lacking.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We used genetic mapping, sequencing, transgenic technology, CRISPR-Cas9 gene editing, immunoblotting, and fluorescence resonance energy transfer. We identified new patients, performed extensive animal phenotyping, and explored new signaling pathways.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              We describe a novel mutation within a 15 base pair (bp) region of the\n              <jats:italic>PDE3A<\/jats:italic>\n              gene and define this segment as a mutational hotspot in hypertension with brachydactyly. The mutations cause an increase in enzyme activity. A CRISPR\/Cas9-generated rat model, with a 9-bp deletion within the hotspot analogous to a human deletion, recapitulates hypertension with brachydactyly. In mice, mutant transgenic PDE3A overexpression in smooth muscle cells confirmed that mutant PDE3A causes hypertension. The mutant PDE3A enzymes display consistent changes in their phosphorylation and an increased interaction with the 14-3-3\u03b8 adaptor protein. This aberrant signaling is associated with an increase in vascular smooth muscle cell proliferation and changes in vessel morphology and function.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>\n              The mutated\n              <jats:italic>PDE3A<\/jats:italic>\n              gene drives mechanisms that increase peripheral vascular resistance causing hypertension. We present 2 new animal models that will serve to elucidate the underlying mechanisms further. Our findings could facilitate the search for new antihypertensive treatments.\n            <\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.119.043061","type":"journal-article","created":{"date-parts":[[2020,6,11]],"date-time":"2020-06-11T09:01:52Z","timestamp":1591866112000},"page":"133-149","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":50,"title":["Phosphodiesterase 3A and Arterial Hypertension"],"prefix":"10.1161","volume":"142","author":[{"given":"Maria","family":"Ercu","sequence":"first","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany (M.E., C.S., S.M., K.Z., N.H., R.H., A.M., B.P., A.G., H.N., S.S., M. Taube, A.H., F.Q., M. Todiras, R.P., E.P., R.L., S.K.F., D.N.M., A.A., M.B., F.C.L., E.K.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (M.E., L.M., C.S., T.U.P.B., N.H., S.K.F., D.N.M., M.B., E.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lajos","family":"Mark\u00f3","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (M.E., L.M., C.S., T.U.P.B., N.H., S.K.F., D.N.M., M.B., E.K.)."},{"name":"Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (L.M., T.U.P.B., N.H., Y.-M.A., S.K.F.)."},{"name":"Experimental and Clinical Research Center, a joint cooperation between the Charit\u00e9 Medical Faculty and the Max-Delbr\u00fcck Center for Molecular Medicine, Berlin, Germany (L.M., C.S., D.T., Y.C., T.U.P.B., R.M.I., S.K.F., I.K., D.N.M., M.G., S.B., F.C.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Sch\u00e4chterle","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany (M.E., C.S., S.M., K.Z., N.H., R.H., A.M., B.P., A.G., H.N., S.S., M. Taube, A.H., F.Q., M. Todiras, R.P., E.P., R.L., S.K.F., D.N.M., A.A., M.B., F.C.L., E.K.)."},{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (M.E., L.M., C.S., T.U.P.B., N.H., S.K.F., D.N.M., M.B., E.K.)."},{"name":"Experimental and Clinical Research Center, a joint cooperation between the Charit\u00e9 Medical Faculty and the Max-Delbr\u00fcck Center for Molecular Medicine, Berlin, Germany (L.M., C.S., D.T., Y.C., T.U.P.B., R.M.I., S.K.F., I.K., D.N.M., M.G., S.B., F.C.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Tsvetkov","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center, a joint cooperation between the Charit\u00e9 Medical Faculty and the Max-Delbr\u00fcck Center for Molecular Medicine, Berlin, Germany (L.M., C.S., D.T., Y.C., T.U.P.B., R.M.I., S.K.F., I.K., D.N.M., M.G., S.B., F.C.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingqiu","family":"Cui","sequence":"additional","affiliation":[{"name":"Experimental and Clinical Research Center, a joint cooperation between the Charit\u00e9 Medical Faculty and the Max-Delbr\u00fcck Center for Molecular Medicine, Berlin, Germany (L.M., C.S., D.T., Y.C., T.U.P.B., R.M.I., S.K.F., I.K., D.N.M., M.G., S.B., F.C.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Maghsodi","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany (M.E., C.S., S.M., K.Z., N.H., R.H., A.M., B.P., A.G., H.N., S.S., M. Taube, A.H., F.Q., M. Todiras, R.P., E.P., R.L., S.K.F., D.N.M., A.A., M.B., F.C.L., E.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theda U.P.","family":"Bartolomaeus","sequence":"additional","affiliation":[{"name":"German Center for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (M.E., L.M., C.S., T.U.P.B., N.H., S.K.F., D.N.M., M.B., E.K.)."},{"name":"Charit\u00e9-Universit\u00e4tsmedizin Berlin, Germany (L.M., T.U.P.B., N.H., Y.-M.A., S.K.F.)."},{"name":"Experimental and Clinical Research Center, a joint cooperation between the Charit\u00e9 Medical Faculty and the Max-Delbr\u00fcck Center for Molecular Medicine, Berlin, Germany (L.M., C.S., D.T., Y.C., T.U.P.B., R.M.I., S.K.F., I.K., D.N.M., M.G., S.B., F.C.L.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philipp G.","family":"Maass","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology Program, Sickkids Research Institute and Department of Molecular Genetics, University of Toronto, ON, Canada (P.G.M.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin","family":"Z\u00fchlke","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany (M.E., C.S., S.M., K.Z., N.H., R.H., A.M., B.P., A.G., H.N., S.S., M. Taube, A.H., F.Q., M. Todiras, R.P., E.P., R.L., S.K.F., D.N.M., A.A., M.B., F.C.L., E.K.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nerine","family":"Gregersen","sequence":"additional","affiliation":[{"name":"Auckland District Health Board (ADHB), Genetic Health Service New Zealand \u2013 Northern Hub (N.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"H\u00fcbner","sequence":"additional","affiliation":[{"name":"Max-Delbr\u00fcck-Center for Molecular Medicine (MDC) in the Helmholtz Association, Berlin, Germany (M.E., C.S., S.M., K.Z., N.H., R.H., A.M., B.P., A.G., H.N., S.S., M. Taube, A.H., F.Q., M. 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