Luteolin reduces necroptosis in the diabetic heart after cardiac arrest and resuscitation by activating sirtuin 3.

Backgrounds: Myocardial impairment resulting from cardiopulmonary resuscitation (CPR) contributes to the elevated mortality in diabetes. Luteolin, a naturally occurring polyphenolic compound abundant in vegetables, fruits, and nuts, has been shown to mitigate myocardial I/R injury in diabetes by suppressing oxidative stress. However, whether luteolin confers cardioprotection following cardiac arrest (CA) and CPR in diabetes remains unclear. Sirtuin 3 (Sirt3), a mitochondrial deacetylase, has been reported to attenuate diabetic cardiomyopathy by reducing oxidative stress and inflammation-mediated necroptosis. Recent evidence suggests that luteolin can upregulate Sirt3 and enhance mitochondrial function. Thus, we hypothesized that luteolin may alleviate post-CA/CPR myocardial injury in diabetes by inhibiting necroptosis through activation of the Sirt3 signaling pathway. Methods: Diabetes was induced in male Sprague-Dawley rats via a single intraperitoneal injection of streptozotocin (65 mg/kg). Rats were then treated with luteolin (100 mg/kg, i.g.) or Sirt3 inhibitor 3-TYP for 2 weeks. Subsequently, diabetic rats were subjected to 5 min of asphyxia-induced CA followed by CPR. After 6 h of resuscitation, left ventricular function, myocardial infarction, oxidative stress markers, inflammatory cytokine release, mitochondrial function, necroptosis-associated protein expression, and both Sirt3 expression and enzymatic activity were assessed. Results: Luteolin significantly improved post-resuscitation cardiac function and reduced myocardial infarction, oxidative stress, and pro-inflammatory cytokine levels in diabetic rats. It also inhibited cytosolic Ca Conclusion: Luteolin protects diabetic hearts after CA/CPR by suppressing necroptosis, primarily through activation of Sirt3, which dampens oxidative stress and inflammation, and maintains mitochondrial integrity.