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<p>Pathological cardiac hypertrophy develops as a maladaptive response to sustained pressure overload, transitioning from compensatory adaptation to dysfunction. Understanding its molecular mechanisms is crucial for developing therapeutic strategies. Here, we identified ovarian tumor (OTU) domain-containing ubiquitin aldehyde-binding protein 2 (OTUB2) as a key regulator of pathological cardiac hypertrophy. OTUB2 expression was significantly upregulated at both transcriptional and translational levels in transverse aortic constriction (TAC)-induced hypertrophic hearts and phenylephrine (PE)-stimulated cardiomyocytes. In vivo, cardiomyocyte-specific OTUB2 overexpression via AAV9 exacerbated TAC-induced cardiac remodeling, manifested by increased heart weight/body weight ratio, impaired ejection fraction, ventricular dilatation, and enhanced fibrosis (as shown by Picrosirius red staining). In neonatal rat cardiomyocytes (NRCMs), OTUB2 overexpression aggravated while its knockdown attenuated PE-induced cardiomyocytes hypertrophy. Mechanistically, OTUB2 upregulated both total and GTP-bound active Rac1, thereby activating the downstream MEK/ERK pathway. Notably, pharmacological inhibition of Rac1 activation&#xa0;with NSC23766 abolished OTUB2-mediated hypertrophic responses in PE-treated cardiomyocytes. Our findings establish the OTUB2/Rac1 axis as a novel regulator of pathological cardiac hypertrophy and a potential therapeutic target for cardiac remodeling.</p>

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OTUB2 aggravates pathological cardiac hypertrophy through Rac1 activation

  • 期刊论文

  • 发表日期：

    2025年12月2日

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  • Junhui Xing,
  • Lijin Lin,
  • Yi Zhao,
  • Zhen Shen,
  • Yuzhen Wei,
  • Xiaofei Xue,
  • Fen Qin,
  • Hengdao Liu

摘要

Pathological cardiac hypertrophy develops as a maladaptive response to sustained pressure overload, transitioning from compensatory adaptation to dysfunction. Understanding its molecular mechanisms is crucial for developing therapeutic strategies. Here, we identified ovarian tumor (OTU) domain-containing ubiquitin aldehyde-binding protein 2 (OTUB2) as a key regulator of pathological cardiac hypertrophy. OTUB2 expression was significantly upregulated at both transcriptional and translational levels in transverse aortic constriction (TAC)-induced hypertrophic hearts and phenylephrine (PE)-stimulated cardiomyocytes. In vivo, cardiomyocyte-specific OTUB2 overexpression via AAV9 exacerbated TAC-induced cardiac remodeling, manifested by increased heart weight/body weight ratio, impaired ejection fraction, ventricular dilatation, and enhanced fibrosis (as shown by Picrosirius red staining). In neonatal rat cardiomyocytes (NRCMs), OTUB2 overexpression aggravated while its knockdown attenuated PE-induced cardiomyocytes hypertrophy. Mechanistically, OTUB2 upregulated both total and GTP-bound active Rac1, thereby activating the downstream MEK/ERK pathway. Notably, pharmacological inhibition of Rac1 activation with NSC23766 abolished OTUB2-mediated hypertrophic responses in PE-treated cardiomyocytes. Our findings establish the OTUB2/Rac1 axis as a novel regulator of pathological cardiac hypertrophy and a potential therapeutic target for cardiac remodeling.