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Plasma levels of atrial and brain natriuretic peptides, encoded by the\n                    <jats:italic>Nppa and Nppb<\/jats:italic>\n                    , respectively, and synthesized predominantly in cardiomyocytes, vary depending on the severity of heart failure. We previously identified the noncoding conserved region 9 (CR9) element as a putative\n                    <jats:italic>Nppb<\/jats:italic>\n                    enhancer at 22\u2010kb upstream from the\n                    <jats:italic>Nppb<\/jats:italic>\n                    gene. However, its regulatory mechanism remains unknown. Here, we therefore investigated the mechanism of CR9 activation in cardiomyocytes using different kinds of drugs that induce either cardiac hypertrophy or cardiac failure accompanied by natriuretic peptides upregulation. Chronic treatment of mice with either catecholamines or doxorubicin increased CR9 activity during the progression of cardiac hypertrophy to failure, which is accompanied by proportional increases in\n                    <jats:italic>Nppb<\/jats:italic>\n                    expression. Conversely, for cultured cardiomyocytes, doxorubicin decreased CR9 activity and\n                    <jats:italic>Nppb<\/jats:italic>\n                    expression, while catecholamines increased both. However, exposing cultured cardiomyocytes to mechanical loads, such as mechanical stretch or hydrostatic pressure, upregulate CR9 activity and\n                    <jats:italic>Nppb<\/jats:italic>\n                    expression even in the presence of doxorubicin. Furthermore, the enhancement of CR9 activity and\n                    <jats:italic>Nppa<\/jats:italic>\n                    and\n                    <jats:italic>Nppb<\/jats:italic>\n                    expressions by either catecholamines or mechanical loads can be blunted by suppressing mechanosensing and mechanotransduction pathways, such as muscle LIM protein (MLP) or myosin tension. Finally, the CR9 element showed a more robust and cell\u2010specific response to mechanical loads than the \u2212520\u2010bp BNP promoter. We concluded that the CR9 element is a novel enhancer that responds to mechanical loads by upregulating natriuretic peptides expression in cardiomyocytes.\n                  <\/jats:p>","DOI":"10.1096\/fj.202002111rr","type":"journal-article","created":{"date-parts":[[2021,3,10]],"date-time":"2021-03-10T11:01:18Z","timestamp":1615374078000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["The CR9 element is a novel mechanical load\u2010responsive enhancer that regulates natriuretic peptide genes expression"],"prefix":"10.1096","volume":"35","author":[{"given":"Yohei","family":"Miyashita","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry Graduate School of Medicine\/Frontier Biosciences Osaka University Suita Japan"},{"name":"Department of Legal Medicine Graduate School of Medicine Osaka University Suita Japan"},{"name":"Department of Cardiovascular Medicine Graduate School of Medicine 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