MsrB2 Deficiency Amplifies ECM-Driven Cardiac Fibrosis Under Hypertensive Stress

Jo Ho Yun¹Suyeon cho²Jong Youl Lee²Suji Kim²Seung Hee Lee^1,3*

• ¹Division of Endocrine and Kidney Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju-si, Republic of Korea
• ²Division of Cardiovascular Disease Research, Department for Chronic Disease Convergence Research, Korea National Institute of Health, Cheongju-si, Republic of Korea
• ³Division of Cardiovascular Disease Research, Department for Chronic Disease Convergence Research, Cheongju-si, Republic of Korea

Background: Methionine sulfoxide reductase B2 (MsrB2), a mitochondrial redox enzyme essential for maint aining protein integrity under oxidative stress, has been implicated in diabetic cardiac remodeli ng. However, its contribution to hypertension-induced fibrosis remains unclear. Hypertension fr equently coexists with diabetes and accelerates cardiac fibrotic remodeling, particularly in non-obese diabetic patients who may exhibit distinct metabolic and oxidative responses. Methods: We investigated the role of MsrB2 in extracellular matrix (ECM)-driven cardiac fibrosis using both animal and human hypertensive heart samples. MsrB2 expression was evaluated in non-o bese (Goto-Kakizaki, GOTO) and obese (OLETF) diabetic rat models and in angiotensin II (Ang II)–infused MsrB2 knockout (KO) mice. Histological, biochemical, and transcriptomic an alyses were performed to assess myocardial fibrosis, fibrosis-related signaling, and redox gene expression. Results: MsrB2 expression was markedly reduced in human hypertensive hearts and in the myocardiu m of non-obese diabetic rats, whereas it remained unchanged in obese diabetes despite similar increases in blood pressure. In MsrB2 KO mice, Ang II infusion provoked extensive interstit ial and perivascular collagen deposition, accompanied by enhanced SMAD2/3 activation and u pregulation of profibrotic ECM genes including Col1a1, Col3a1, COMP, and LOX. Transcript omic profiling revealed strong enrichment of extracellular matrix and collagen-related pathway s, along with increased expression of oxidative/inflammatory mediators such as Spp1 and Ccr 2, while antioxidant and mitochondrial quality-control genes (Sdhaf2, Rnls, Mapk8) were suppr essed. These results indicate that MsrB2 deficiency shifts the myocardium toward a pro-oxida nt and pro-fibrotic phenotype under hypertensive stress. Conclusion: Loss of MsrB2 amplifies ECM-driven cardiac fibrosis during hypertensive stress by promoting oxidative imbalance and SMAD2/3 activation. In non-obese diabetes, the concomitant reductio n of MsrB2 expression may further accelerate hypertensive remodeling, highlighting a mechani sm that could explain the higher incidence of cardiovascular complications observed in non-ob ese diabetic individuals. These findings identify MsrB2 as a critical redox regulator that restra ins ECM-driven fibrosis and suggest that enhancing its activity could represent a therapeutic a pproach to prevent metabolic and hypertensive cardiac disease.