Ankrd1 knockdown or blockade of its nuclear translocation rescued cardiac dysfunction, reduced injury biomarkers, and improved survival in murine models of septic cardiomyopathy.
Does Ankrd1 knockdown or blockade of its nuclear translocation improve cardiac function and survival in models of septic cardiomyopathy?
Ankrd1 exacerbates septic cardiomyopathy via TNFα-driven NF-κB activation, and its knockdown or nuclear import blockade rescues cardiac function and improves survival in preclinical models.
Absolute Event Rate: 0% vs 0%
Introduction: Septic myocardial injury, the most prevalent organ dysfunction in sepsis, manifests as acute impairment of both systolic and diastolic cardiac function. Pro-inflammatory cytokines (e.g., TNFα, IL-1β, IL-6), released by immune cells, are well-established to directly suppress cardiomyocyte contractility. Ankrd1 is recognized as a biomarker of structural and functional cardiac damage, with its expression robustly upregulated by cellular stress and inflammatory stimuli. Emerging evidence also implicates Ankrd1 in regulating cardiomyocyte cell cycle progression and regeneration. However, the specific role and functional significance of Ankrd1 within the context of septic cardiomyopathy remain incompletely defined and warrant further investigation. Methods: Utilizing C57BL/6J mice and neonatal rat ventricular myocytes (NRVMs), we assessed target molecule expression/localization via Western blotting (WB), qRT-PCR, and immunofluorescence (IF). Cardiac injury biomarkers in serum/cell media were measured by ELISA. Cardiac function was evaluated in vivo using echocardiography and in vitro via myocyte contractility assays. Ankrd1 expression was knocked down using AAV9 (in vivo) and siRNA (in vitro). Ivermectin was employed to modulate Ankrd1 nuclear translocation. Results: Ankrd1 expression was significantly upregulated in cardiac tissue from both CLP- and LPS-induced murine sepsis models. In vitro, TNFα (100 pg/mL), but not LPS or IL-1β, robustly induced Ankrd1 expression and promoted its nuclear translocation in NRVMs. siRNA-mediated Ankrd1 knockdown attenuated TNFα-induced elevations in cardiac injury biomarkers (cTnI, CK-MB) and NF-κB pathway activation. RNA sequencing further implicated Ankrd1 in TNFα-driven inflammatory signaling and contractile dysfunction. Critically, in vivo interventions via AAV9-mediated Ankrd1 knockdown or Ivermectin-induced blockade of Ankrd1 nuclear import effectively rescued LPS-induced cardiac dysfunction, reduced serum cTnI/CK-MB levels, and improved survival. Conclusions: TNFα predominantly mediates Ankrd1 upregulation in septic myocardial injury. Nuclear translocation of Ankrd1 exacerbates cardiac damage by modulating inflammatory signaling pathways, including NF-κB activation.
Wang et al. (Sun,) reported a other. Ankrd1 knockdown or blockade of its nuclear translocation rescued cardiac dysfunction, reduced injury biomarkers, and improved survival in murine models of septic cardiomyopathy.