Key result
Cardiomyocyte Contactin-2 knockout worsens heart failure in mice, reducing LVEF by ~17%.
Why the study?
The roles of Contactin-2 and ferroptosis in heart failure and cardiac remodeling remain incompletely understood.
Does CNTN2 or NUPR1 overexpression mitigate heart failure, cardiac remodeling, and ferroptosis in pressure overload-induced heart failure models?
Does CNTN2 or NUPR1 overexpression mitigate heart failure, cardiac remodeling, and ferroptosis in pressure overload-induced heart failure models?
Answers are grounded in this paper and cite their sources.
CNTN2 protects against pressure overload-induced heart failure and cardiac remodeling by regulating ferroptosis through the Lyn/eIF2α/ATF4/NUPR1 pathway, highlighting it as a potential therapeutic target.
The roles of Contactin-2 (CNTN2) and ferroptosis in heart failure and cardiac remodeling remain incompletely understood. CNTN2 was significantly upregulated in hypertrophic cardiomyopathy patients and heart failure mice. In cardiomyocyte specific CNTN2 conditional knockout (CNTN2 cKO) mice, transverse aortic constriction (TAC) induced markedly exacerbated heart failure, cardiac remodeling and ferroptosis compared to control mice. Ferroptosis inhibition substantially attenuated heart failure in CNTN2 cKO mice subjected to TAC, indicating that enhanced ferroptosis contributes to the detrimental effects of CNTN2 deficiency. RNA sequencing identified NUPR1, a ferroptosis repressor, as a downstream molecule of CNTN2. Mechanistically, CNTN2 activated the Lyn/eIF2α/ATF4 pathway to regulate NUPR1. CNTN2 overexpression attenuated Angiotensin II-induced cardiomyocyte ferroptosis and pathological remodeling, whereas these protective effects were abolished by Lyn or NUPR1 inhibitors. We further revealed CNTN2 and Lyn interacted with each other, and that CNTN2 interacted with Lyn through its 1-328aa domain. In vivo NUPR1 overexpression via AAV9 significantly mitigated TAC-induced heart failure and cardiac remodeling in CNTN2 cKO mice. Our study demonstrates that CNTN2 protects against pressure overload induced heart failure and cardiac remodeling by regulating ferroptosis through the Lyn/eIF2α/ATF4/NUPR1 pathway, suggesting CNTN2 as a potential therapeutic target.
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Fei et al. (2026) studied Heart failure and cardiac remodeling. Cardiomyocyte-specific CNTN2 conditional knockout vs. CNTN2flox/flox (control) mice was evaluated on Ejection fraction (p=0.010). Cardiomyocyte-specific Contactin-2 conditional knockout significantly exacerbated heart failure in mice subjected to transverse aortic constriction, reducing ejection fraction to 38.5% compared to 46.2% in control mice.
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