{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T05:20:29Z","timestamp":1787721629975,"version":"build-2784847793"},"reference-count":71,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"13","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["JAHA"],"published-print":{"date-parts":[[2026,7,7]]},"abstract":"<jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">The effects of TGF\u2010\u03b2s (transforming growth factor\u2010\u03b2s) in failing hearts involve cell\u2010specific actions mediated through receptor\u2010regulated Smads or Smad\u2010independent pathways. The inhibitory Smad, Smad7, is a negative feedback regulator that restrains excessive TGF\u2010\u03b2\/receptor\u2010regulated Smad signaling, while also exerting TGF\u2010\u03b2\u2013independent effects. We hypothesized that cardiomyocyte Smad7 upregulation contributes to the pathogenesis of pressure overload\u2013induced heart failure and investigated the mechanisms underlying its actions.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Cardiomyocyte\u2010specific Smad7 knockout mice and corresponding Cre+ and Smad7\n                      <jats:sup>fl\/fl<\/jats:sup>\n                      controls underwent transverse aortic constriction. Echocardiographic, histological, transcriptomic, and proteomic analyses were performed. RNA sequencing identified candidate pathways modulated by Smad7. Effects of Smad7 loss on TGF\u2010\u03b2 and ERBB2 (erb\u2010b2 receptor tyrosine kinase 2) cascades were examined in\u00a0vivo and in cardiomyocyte\u2010like H9c2 cells using western blotting.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Smad7 was upregulated in cardiomyocytes and fibroblasts following transverse aortic constriction and in patients with nonischemic cardiomyopathy. Cardiomyocyte\u2010specific Smad7 knockout mice had no baseline abnormalities but developed worse systolic and diastolic dysfunction and increased cardiomyocyte hypertrophy after pressure overload. Cardiomyocyte Smad7 loss did not alter fibrosis after transverse aortic constriction but increased macrophage infiltration. Cardiomyocyte\u2010specific Smad7 knockout hearts showed reduced expression of genes associated with cardiac contraction. Bioinformatic analysis identified TGF\u2010\u03b21, angiotensin, and ERBB2 as candidate upstream regulators mediating the effects of Smad7 loss. In\u00a0vivo, cardiomyocyte Smad7 inhibited activation of\n                      <jats:styled-content style=\"fixed-case\" toggle=\"no\">TGF\u2010\u03b2 receptor 1 (<\/jats:styled-content>\n                      TGFBR1)\/Smad2\/3 and ERBB2 without affecting\n                      <jats:styled-content style=\"fixed-case\" toggle=\"no\">TGF\u2010\u03b2 receptor 2 (<\/jats:styled-content>\n                      TGFBR2) activity. In the absence of Smad7, pressure\u2010overloaded cardiomyocytes exhibited increased TGFBR1\/Smad3 activation. In H9c2 cells, endogenous Smad7 restrained TGFBR1\/Smad3 activation without affecting TGFBR2 or ERBB2 activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">Cardiomyocyte Smad7 protects the pressure\u2010overloaded heart from dysfunction, regulating genes involved in muscle contraction, likely through direct suppression of TGFBR1\/Smad3.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/jaha.125.045203","type":"journal-article","created":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T10:15:03Z","timestamp":1783073703000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Cardiomyocyte\u2010Specific Smad7 Protects the Pressure\u2010Overloaded Heart, Inhibiting the Transforming Growth Factor\u2010\u03b2 Receptor 1\/Smad2\/3 Cascade"],"prefix":"10.1161","volume":"15","author":[{"given":"Claudio","family":"Humeres","sequence":"first","affiliation":[{"name":"Albert Einstein College of Medicine","place":["Bronx, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8482-591X","authenticated-orcid":false,"given":"Izabela","family":"Tuleta","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine","place":["Bronx, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9718-8155","authenticated-orcid":false,"given":"Dongze","family":"Qin","sequence":"additional","affiliation":[{"name":"Albert Einstein College of Medicine","place":["Bronx, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3953-4029","authenticated-orcid":false,"given":"Arti V.","family":"Shinde","sequence":"additional","affiliation":[{"name":"Albert Einstein College of 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