• Modeling Mechanism：

  Norepinephrine hydrochloride works synergistically with lipopolysaccharide (LPS) to induce cardiomyopathy through SIRT3/HO-1 axis-mediated ferroptosis: ① NE alone has no significant cardiotoxicity, but it can exacerbate LPS-induced oxidative stress, increasing reactive oxygen species (ROS) and lipid peroxidation levels (4-HNE and MDA are elevated); ② It inhibits SIRT3 activity, relieves its inhibition of p300, promotes HO-1 acetylation and enhances stability, accelerates heme degradation and releases ferrous ions, and induces iron overload; ③ Iron overload and lipid peroxidation together induce cardiomyocyte ferroptosis, accompanied by myocardial hypertrophy and fibrosis, ultimately leading to heart failure.

• Related Products：

  Norepinephrine hydrochloride (T60245)

• Modeling Method：

  Experimental Subject：

  Mice, C57BL/6, 8–12 weeks old, Body weight 25–28 g

  Dosage and Administration Route：

  ① Core modelling (two-hit protocol):
  - First challenge: Intraperitoneal (i.p.) injection of LPS at 5 mg/kg, single dose;
  - Second challenge: Simultaneous LPS administration with subcutaneous implantation of osmotic pump; Norepinephrine at 2 µg/kg/min via continuous infusion for 9 days;
  ② Control treatment:
  - LPS-only group: intraperitoneal injection of 5 mg/kg LPS+osmotic pump infusion of physiological saline;
  - NE-only group: Intraperitoneal injection of physiological saline+osmotic pump infusion of 2 µg/kg/min Norepinephrine;
  - Blank control: Intraperitoneal injection of saline+osmotic pump infusion of saline;
  ③ Intervention validation group (optional):
  - Ferroptosis inhibitor: Ferrostatin-1 (Fer-1), 2 mg/kg/day, intraperitoneal injection, administered concurrently with modelling;
  - SIRT3 activator: 2-APQC, 30 mg/kg, intraperitoneal injection, administered continuously throughout modelling period

  Dosing Frequency and Duration Model：

  First strike: single-dose administration;
  Secondary challenge: Continuous infusion for 9 days

• Validation：

  1. Pathological Indicators: - Myocardial Injury: HE staining showed cardiomyocyte hypertrophy (cross-sectional area increased by more than 250), and Masson staining showed an increased proportion of interstitial fibrosis area (p<0.01); - Ferroplasmosis Characteristics: Transmission electron microscopy showed mitochondrial shrinkage, DHE staining showed increased ROS levels (fluorescence intensity more than 3 times that of the control group), and significantly increased ferrous ion content in tissues (OD value ≥0.4, p<0.001); 2. Molecular Indicators: - Ferroplasmosis Pathway: Western blot showed upregulated expression of HO-1 and 4-HNE proteins and downregulated expression of SIRT3 (p<0.01); - Myocardial Markers: Serum troponin T (cTnT) and creatine kinase isoenzyme (CK-MB) levels were significantly increased (p<0.001); 3. Functional Indicators: - Cardiac Function: Echocardiography showed that the left ventricular ejection fraction (EF%) decreased to below 60% (control group ≥80%, p<0.01); Survival status: The 9-day survival rate after modeling was more than 30% lower than that of the LPS group alone (p<0.05).

*Precautions：

*References：Ma D,et,al. Norepinephrine exacerbates LPS-induced cardiomyopathy via SIRT3/HO-1 axis-mediated ferroptosis. Crit Care. 2025 Aug 13;29(1):354.