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Canagliflozin attenuates post-resuscitation myocardial dysfunction in diabetic rats by inhibiting autophagy through

Qihui Huang1,2, Wei Shi1,2, Minjie Wang1,2

  • 1The Second Department of Intensive Care Unit, The Second Affiliated Hospital of Anhui Medical University, Hefei 230601, Anhui, People's Republic of China.

Iscience
|August 6, 2024
PubMed

Insights

Canagliflozin improves heart function after cardiac arrest in diabetic rats by reducing damage and preserving mitochondria. This suggests potential for treating post-resuscitation myocardial dysfunction in diabetes.

Area of Science:

  • Cardiology
  • Diabetology
  • Pharmacology

Background:

  • Cardiac arrest and cardiopulmonary resuscitation (CPR) can lead to myocardial dysfunction, especially in patients with type 2 diabetes mellitus (T2DM).
  • Diabetic cardiomyopathy exacerbates cardiac injury following resuscitation, increasing morbidity and mortality.
  • Understanding protective mechanisms against post-resuscitation myocardial dysfunction in diabetes is crucial for therapeutic development.

Purpose of the Study:

  • To investigate the protective effects of canagliflozin on myocardial dysfunction in a rat model of cardiac arrest and CPR.
  • To elucidate the underlying mechanisms, including mitochondrial function and autophagy, involved in canagliflozin's cardioprotective effects in diabetic hearts.
  • To explore the role of the PI3K/Akt/mTOR pathway in mediating canagliflozin's benefits.

Main Methods:

  • Type 2 diabetes mellitus (T2DM) was induced in male rats, followed by a cardiac arrest and CPR model.
  • Rats were pretreated with canagliflozin (10 mg/kg/day) for four weeks prior to the procedure.
  • Measurements included ATP levels, ejection fraction, acidosis, hemodynamics, myocardial edema, mitochondrial damage, autophagy, reactive oxygen species (ROS), and mitochondrial membrane potential.
  • In vitro studies utilized a PI3K/Akt pathway inhibitor (Ly294002) to assess pathway activation.

Main Results:

  • Canagliflozin pretreatment significantly improved post-resuscitation ejection fraction, acidosis, and hemodynamic parameters.
  • It reduced myocardial edema, mitochondrial damage, and excessive autophagy levels.
  • In vitro, canagliflozin decreased ROS production and preserved mitochondrial membrane potential.
  • Canagliflozin attenuated high glucose and hypoxia-reoxygenation-induced cardiac injury by activating the PI3K/Akt/mTOR pathway.

Conclusions:

  • Canagliflozin demonstrates significant cardioprotective effects against myocardial dysfunction following cardiac arrest and CPR in diabetic rats.
  • The drug mitigates injury by preserving mitochondrial function, reducing oxidative stress, and modulating autophagy via the PI3K/Akt/mTOR pathway.
  • These findings suggest canagliflozin holds therapeutic promise for managing post-resuscitation cardiac complications in diabetic patients.
Keywords:
cardiovascular medicinehuman metabolism

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