Calotropin attenuates ischemic heart failure after myocardial infarction by modulating SIRT1/FOXD3/SERCA2a pathway

Area of Science:

• Cardiovascular Research
• Pharmacology
• Molecular Biology

Background:

• Heart failure (HF) is a severe cardiovascular condition with limited treatments.
• Calotropin (CAL), a cardenolide from Calotropis gigantea, shows potential due to its similarity to digoxin.
• The therapeutic effects of CAL on ischemic heart failure (IHF) are not well understood.

Purpose of the Study:

• To investigate the anti-HF effects of CAL in an IHF model.
• To elucidate the underlying molecular mechanisms of CAL's action.

Main Methods:

• An ischemic heart failure (IHF) model was created in rats by ligating the left anterior descending artery.
• Calotropin (CAL) was administered daily to IHF rats.
• H9c2 cells were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to mimic ischemic injury.
• Expression levels of SERCA2a and SIRT1 were analyzed.
• The role of SIRT1 was assessed using the inhibitor EX527.
• FOXD3's involvement was investigated.

Main Results:

• CAL administration significantly improved ejection fraction (EF) and fractional shortening (FS) in IHF rats.
• CAL treatment reduced cardiac fibrosis and protected H9c2 cells from OGD/R-induced injury.
• CAL upregulated the expression of SERCA2a and SIRT1.
• The protective effects of CAL were diminished when SIRT1 was inhibited.
• CAL promoted SIRT1-dependent deacetylation and nuclear translocation of FOXD3, a key transcription factor for SERCA2a regulation.

Conclusions:

• Calotropin demonstrates significant cardioprotective effects against ischemic heart failure.
• CAL acts by modulating the SIRT1/FOXD3/SERCA2a pathway, enhancing cardiac function and reducing fibrosis.
• This study reveals a novel therapeutic mechanism for CAL in treating heart failure.