What is the clinical evidence from this study?

Study design: Other. Population: Cardiac fibrosis under hypertensive stress. Intervention: Angiotensin II (Ang II) infusion vs. Wild-type controls (PBS). Primary outcome: Cardiac fibrosis measured by histology and fibrosis-related marker analysis (null, 95% CI null, p=null).

What does this research mean for the field?

MsrB2 deficiency amplifies ECM-driven cardiac fibrosis during hypertensive stress by promoting oxidative imbalance and SMAD2/3 activation. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.CHALLENGES_CONSENSUS.

What question did this study set out to answer?

This research aims to clarify the role of MsrB2 in ECM-driven cardiac fibrosis under hypertensive stress.

March 16, 2026Open Access

MsrB2 deficiency amplifies ECM-driven cardiac fibrosis under hypertensive stress

Key Result

MsrB2 knockout mice exhibited extensive cardiac fibrosis and enhanced SMAD2/3 activation under Angiotensin II infusion compared to wild-type controls, indicating MsrB2 deficiency amplifies ECM-driven cardiac fibrosis during hypertensive stress.

Key Points

This research aims to clarify the role of MsrB2 in ECM-driven cardiac fibrosis under hypertensive stress.
Evaluated MsrB2 expression in human hypertensive hearts and diabetic rat models.
Used Ang II-infused MsrB2 knockout mice to assess fibrosis response.
Performed histological, biochemical, and transcriptomic analyses to measure myocardial fibrosis and related signaling.
Reduced MsrB2 expression in hypertensive human hearts and non-obese diabetic rats.
In MsrB2 KO mice, Ang II infusion led to significant collagen deposition and SMAD2/3 activation.
Transcriptomic profiling showed enrichment of ECM and collagen-related pathways and suppressed antioxidant genes.

Structured PICO

Does MsrB2 deficiency amplify ECM-driven cardiac fibrosis under hypertensive stress in animal models?

Population

Human hypertensive heart samples, non-obese (Goto-Kakizaki, GOTO) and obese (OLETF) diabetic rat models with respective controls, and wild-type (WT) and MsrB2 knockout (KO) mice (C57BL/6 J background, male, 10-12 weeks old).

Intervention

Angiotensin II (AngII) infusion (1.5 μg/kg/min) for 2 weeks via osmotic minipumps in MsrB2 KO mice.

Comparator

Wild-type mice with PBS or AngII infusion, and MsrB2 KO mice with PBS infusion.

Outcome

Myocardial fibrosis, SMAD2/3 activation, and expression of profibrotic ECM and redox genes.surrogate

MsrB2 deficiency amplifies ECM-driven cardiac fibrosis during hypertensive stress, identifying MsrB2 as a critical redox regulator and potential therapeutic target for hypertensive heart disease.

Main Result

Effect estimate: null (95% CI null)

p-value: p=null

Limitations

Blood pressure measured using noninvasive tail-cuff method which may be less precise than telemetry-based monitoring.
Potential fibrotic mediators COMP and SPP1 were identified but not mechanistically interrogated; their causal involvement remains to be validated.
MsrB2-dependent mitochondrial signaling was not directly evaluated.

Abstract

Background Methionine sulfoxide reductase B2 (MsrB2), a mitochondrial redox enzyme essential for maintaining protein integrity under oxidative stress, has been implicated in diabetic cardiac remodeling. However, its contribution to hypertension-induced fibrosis remains unclear. Hypertension frequently 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-obese (Goto-Kakizaki, GOTO) and obese (OLETF) diabetic rat models and in angiotensin II (Ang II)–infused MsrB2 knockout (KO) mice. Histological, biochemical, and transcriptomic analyses 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 myocardium 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 interstitial and perivascular collagen deposition, accompanied by enhanced SMAD2/3 activation and upregulation of profibrotic ECM genes including Col1a1 , Col3a1 , COMP , and LOX . Transcriptomic profiling revealed strong enrichment of extracellular matrix and collagen-related pathways, along with increased expression of oxidative/inflammatory mediators such as Spp1 and Ccr2 , while antioxidant and mitochondrial quality-control genes ( Sdhaf2 , Rnls , Mapk8 ) were suppressed. These results indicate that MsrB2 deficiency shifts the myocardium toward a pro-oxidant 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 reduction of MsrB2 expression may further accelerate hypertensive remodeling, highlighting a mechanism that could explain the higher incidence of cardiovascular complications observed in non-obese diabetic individuals. These findings identify MsrB2 as a critical redox regulator that restrains ECM-driven fibrosis and suggest that enhancing its activity could represent a therapeutic approach to prevent metabolic and hypertensive cardiac disease.

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