{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:10:43Z","timestamp":1790251843185,"version":"4.1.0"},"reference-count":46,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T00:00:00Z","timestamp":1608768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2017R1A5A2015805"],"award-info":[{"award-number":["2017R1A5A2015805"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2018R1D1A1B07050720"],"award-info":[{"award-number":["2018R1D1A1B07050720"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Cardiac hypertrophy is a major risk factor for heart failure and leads to cardiovascular morbidity and mortality. Doxorubicin (DOX) is regarded as one of the most potent anthracycline antibiotic agents; however, its clinical usage has some limitations because it has serious cardiotoxic side effects such as dilated cardiomyopathy and congestive heart failure. Betulinic acid (BA) is a pentacyclic-cyclic lupane-type triterpene that has been reported to have anti-bacterial, anti-inflammatory, anti-vascular neogenesis, and anti-fibrotic effects. However, there is no study about its direct effect on DOX induced cardiac hypertrophy and apoptosis. The present study aims to investigate the effect of BA on DOX-induced cardiomyocyte hypertrophy and apoptosis in vitro in H9c2 cells. The H9c2 cells were stimulated with DOX (1 \u00b5M) in the presence or absence of BA (0.1\u20131 \u03bcM) and incubated for 24 h. The results of the present study indicated that DOX induces the increase cell surface area and the upregulation of hypertrophy markers including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), beta-myosin heavy chain (\u03b2-MHC), and Myosin Light Chain-2 (MLC2) in H9c2 cells. However, the pathological hypertrophic responses were downregulated after BA treatment. Moreover, phosphorylation of JNK, ERK, and p38 in DOX treated H9c2 cells was blocked by BA. As a result of measuring the change in ROS generation using DCF-DA, BA significantly inhibited DOX-induced the production of intracellular reactive oxygen species (ROS) when BA was treated at a concentration of over 0.1 \u00b5M. DOX-induced activation of GATA-4 and calcineurin\/NFAT-3 signaling pathway were remarkably improved by pre-treating of BA to H9c2 cells. In addition, BA treatment significantly reduced DOX-induced cell apoptosis and protein expression levels of Bax and cleaved caspase-3\/-9, while the expression of Bcl-2 was increased by BA. Therefore, BA can be a potential treatment for cardiomyocyte hypertrophy and apoptosis that lead to sudden heart failure.<\/jats:p>","DOI":"10.3390\/molecules26010053","type":"journal-article","created":{"date-parts":[[2020,12,24]],"date-time":"2020-12-24T09:02:44Z","timestamp":1608800564000},"page":"53","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Betulinic Acid Protects DOX-Triggered Cardiomyocyte Hypertrophy Response through the GATA-4\/Calcineurin\/NFAT Pathway"],"prefix":"10.3390","volume":"26","author":[{"given":"Jung Joo","family":"Yoon","sequence":"first","affiliation":[{"name":"Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"},{"name":"College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan Ok","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, School of Medicine, Konkuk University, Gwangjin-gu, Seoul 05029, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0396-0862","authenticated-orcid":false,"given":"Hye Yoom","family":"Kim","sequence":"additional","affiliation":[{"name":"Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"},{"name":"College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Byung Hyuk","family":"Han","sequence":"additional","affiliation":[{"name":"Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"},{"name":"College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9347-8606","authenticated-orcid":false,"given":"Yun Jung","family":"Lee","sequence":"additional","affiliation":[{"name":"Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"},{"name":"College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ho Sub","family":"Lee","sequence":"additional","affiliation":[{"name":"Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"},{"name":"College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dae Gill","family":"Kang","sequence":"additional","affiliation":[{"name":"Hanbang Cardio-Renal Syndrome Research Center, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"},{"name":"College of Oriental Medicine and Professional, Graduate School of Oriental Medicine, Wonkwang University, 460, Iksan-daero, Iksan, Jeonbuk 54538, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1007\/s12012-007-0015-3","article-title":"Role of anthracyclines in the era of targeted therapy","volume":"7","author":"Coronado","year":"2007","journal-title":"Cardiovasc. 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