OTUB2 aggravates pathological cardiac hypertrophy through Rac1 activation

Area of Science:

• Cardiology
• Molecular Biology
• Biochemistry

Background:

• Pathological cardiac hypertrophy is a maladaptive response to pressure overload, progressing to heart dysfunction.
• Understanding the molecular drivers of cardiac hypertrophy is essential for developing effective treatments.

Purpose of the Study:

• To identify novel molecular regulators of pathological cardiac hypertrophy.
• To elucidate the role of ovarian tumor (OTU) domain-containing ubiquitin aldehyde-binding protein 2 (OTUB2) in cardiac hypertrophy.

Main Methods:

• Utilized transverse aortic constriction (TAC) in mice and phenylephrine (PE) stimulation in neonatal rat cardiomyocytes (NRCMs).
• Investigated OTUB2 expression changes and functional impacts of its overexpression or knockdown.
• Assessed cardiac remodeling, fibrosis, and cardiomyocyte size.
• Examined the involvement of the Rac1/MEK/ERK pathway and used Rac1 inhibitor NSC23766.

Main Results:

• OTUB2 expression was significantly upregulated in TAC-induced hypertrophy and PE-stimulated cardiomyocytes.
• Cardiomyocyte-specific OTUB2 overexpression exacerbated TAC-induced cardiac remodeling and fibrosis.
• OTUB2 knockdown attenuated PE-induced cardiomyocyte hypertrophy.
• OTUB2 upregulated active Rac1, activating the MEK/ERK pathway, and Rac1 inhibition blocked OTUB2's hypertrophic effects.

Conclusions:

• OTUB2 acts as a key regulator of pathological cardiac hypertrophy.
• The OTUB2/Rac1/MEK/ERK signaling axis is a novel pathway implicated in cardiac remodeling.
• Targeting the OTUB2/Rac1 axis presents a potential therapeutic strategy for cardiac hypertrophy and remodeling.