NRF2 Inhibits Cardiomyocyte Pyroptosis Via Regulating CTRP1 in Sepsis-Induced Myocardial Injury

Abstract

C1q/tumor necrosis factor-related protein 1 (CTRP1) has been demonstrated as a crucial regulator in myocardial injury (MI). The present study aims to evaluate the mechanism of CTRP1 in sepsis-induced MI. The septic mouse model was established via cecal ligation and puncture and the in vitro cell model was established via lipopolysaccharide treatment. The mouse survival rate within 96 h was recorded. Morphologic changes of cardiomyocytes were observed and cell viability and cardiac functions were detected. CTRP1 and nuclear factor erythroid 2-related factor (Nrf2) expressions, creatine troponin-T, and creatine phosphokinase isoenzyme levels, and expressions of pyroptotic markers were determined. The binding relationship between Nrf2 and the CTRP1 promotor was predicted and verified. Rescue experiments were designed to confirm the role of CTRP1. CTRP1 was poorly expressed in septic mice. CTRP1 overexpression inhibited cardiomyocyte pyroptosis and improved cardiac functions, MI, and survival rate in septic mice. Nrf2was decreased in cecal ligation and puncture -treated mice. Nrf2 overexpression promoted CTRP1 expression via binding to the CTRP1 promotor and suppressed cardiomyocyte pyroptosis. CTRP1 downregulation abolished the inhibitory effect of Nrf2 overexpression on cardiomyocyte pyroptosis. Overall, Nrf2 promoted CTRP1 expression via binding to the CTRP1 promotor to inhibit cardiomyocyte pyroptosis, thereby alleviating MI in septic mice.

Recombinant human angiotensin-converting enzyme 2 plays a protective role in mice with sepsis-induced cardiac dysfunction through multiple signaling pathways dependent on converting angiotensin II to angiotensin 1–7

“…Disturbance of energy metabolism due to either mitochondrial dysfunction or substrate utilization disorder is hot topic in researches (50,51). Though cell death is not the significant character in septic heart, different forms of programmed myocardial cell death including apoptosis, pyroptosis, and ferroptosis have been being investigated because of their influence on inflammation and mitochondrial function (52)(53)(54)(55)(56). The RAAS has been a focus of research for the complex crosstalk among the components and the robust association with heart disease (19,57,58).…”

Molecular mechanisms and functions of pyroptosis in sepsis and sepsis-associated organ dysfunction

“…Similarly, Rahim et al revealed that melatonin can ameliorate sepsisinduced myocardial injury by activating the Nrf2-related pathway and inhibiting the formation of the NLRP3 inflammasome (Rahim et al, 2021). Teng et al found that, in addition to inhibiting ROS, Nrf2 could have a protective role by upregulating C1q/tumor necrosis factor-related protein 1 (CTRP1) expression and inhibiting pyroptosis by binding to the promoter of CTRP1 in sepsis-induced myocardial injury in vivo and in vitro (Teng et al, 2022). CTRP1 is a homologue of adiponectin.…”

“…According to the Human Protein Atlas, each member of the gasdermins family exhibits distinct tissue expression (Supplementary Figure 1). Notably, during sepsis, the protein expression of GSDMA-NT, GSDMD-NT and GSDME-NT are reported to increase in sepsis-associated organ injuries, indicating that pyroptosis could play important roles in sepsis (Chen L. et al, 2021b;Teng et al, 2022). Depending on the inflammatory caspases involved, pyroptosis can be divided into the canonical pathway mediated by caspase-1, and the noncanonical pathway mediated by caspase-4, -5, or -11 (Kayagaki et al, 2015;Shi et al, 2015).…”

Research Progress on the Mechanism of Sepsis Induced Myocardial Injury

“…When sepsis occurs, low expression of Nrf2 leads to non-activation of CTRP1 binding sites, thus inducing pyroptosis of cardiomyocytes. 168 …”

“…When sepsis occurs, low expression of Nrf2 leads to non-activation of CTRP1 binding sites, thus inducing pyroptosis of cardiomyocytes. 168 Previous studies have researched the mechanism of pyroptosis from genomics and laid a foundation for the treatment of SIMI. LncRNA x-inactive specific transcript (XIST) contributes to the treatment of SIMI by affecting pyroptosis mediated by miR-150-5p/c-Fos axis.…”