Key result
Hsp90b1 deficiency improves post-MI survival and cardiac function by curbing cardiomyocyte pyroptosis in mice.
Why the study?
Excessive inflammation drives adverse cardiac remodeling after myocardial infarction, but the mechanisms linking cardiomyocyte injury to immune activation and the specific role of the endoplasmic reticulum chaperone HSP90B1 remain incompletely understood.
Does deficiency or inhibition of HSP90B1 reduce cardiomyocyte pyroptosis, M1-like macrophage polarization, and adverse cardiac remodeling in preclinical models of myocardial infarction?
Does deficiency or inhibition of HSP90B1 reduce cardiomyocyte pyroptosis, M1-like macrophage polarization, and adverse cardiac remodeling in preclinical models of myocardial infarction?
This preclinical study identifies the endoplasmic reticulum chaperone HSP90B1 as a driver of post-MI cardiomyocyte pyroptosis via NF-κB/NLRP3 signaling and M1-like macrophage polarization, suggesting it as a potential therapeutic target to attenuate adverse cardiac remodeling.
Hsp90b1 targeting may limit post-MI remodeling in mice; leaves open translation to human therapy.
Background Excessive inflammation contributes to adverse cardiac remodeling after myocardial infarction (MI), but the mechanisms linking cardiomyocyte injury to immune activation remain incompletely understood. Here, we investigated the role of the endoplasmic reticulum chaperone HSP90B1 in cardiomyocyte injury and inflammatory crosstalk after MI. Methods We examined HSP90B1 expression in human myocardial tissues, mouse MI hearts, and oxygen-glucose deprivation (OGD)-treated AC16 cardiomyocytes. Hsp90b1+/− mice were used to evaluate post-MI survival, cardiac function, and myocardial remodeling. HSP90B1 was selectively silenced or overexpressed in AC16 cardiomyocytes, and transcriptomic and pharmacological analyses were performed to investigate the signaling pathways involved. A non-contact Transwell co-culture system was also established to assess the effects of cardiomyocyte HSP90B1 on macrophage inflammatory activation. Results HSP90B1 was increased in human and mouse myocardial tissues after MI and in OGD-treated AC16 cardiomyocytes. Hsp90b1+/− mice showed improved post-MI survival, preserved cardiac function, and reduced adverse remodeling. In AC16 cardiomyocytes, HSP90B1 promoted OGD-induced pyroptosis and was associated with activation of NF-κB/NLRP3 signaling, whereas pharmacological inhibition of these pathways reduced pyroptosis-related responses. In a non-contact cardiomyocyte–macrophage co-culture system, cardiomyocyte HSP90B1 expression influenced the pro-inflammatory phenotype of macrophages. Conclusions Our findings identify HSP90B1 as a key regulator of cardiomyocyte pyroptotic signaling and post-MI inflammatory remodeling, with cardiomyocyte HSP90B1 expression associated with M1-like macrophage polarization.
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Wang et al. (2026) studied Myocardial infarction (n=16). HSP90B1 expression and genetic/pharmacological modulation (Hsp90b1+/- deficiency, siRNA knockdown, overexpression) vs. Wild-type controls, sham surgery, or negative control vector/siRNA was evaluated on Post-MI survival, left ventricular function (EF, FS, LVIDd, LVIDs), myocardial fibrosis, and NF-kB/NLRP3-mediated cardiomyocyte pyroptosis (p=<0.05). Hsp90b1 deficiency improved post-MI survival and cardiac function in mice while reducing cardiomyocyte pyroptosis via NF-κB/NLRP3 signaling and attenuating M1-like macrophage polarization.
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