Luteolin Exerts Cardioprotective Effects through Improving Sarcoplasmic Reticulum Ca²⁺-ATPase Activity in Rats during Ischemia/Reperfusion In Vivo

Abstract

The flavonoid luteolin exists in many types of fruits, vegetables, and medicinal herbs. Our previous studies have demonstrated that luteolin reduced ischemia/reperfusion (I/R) injury in vitro, which was related with sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. However, the effects of luteolin on SERCA2a activity during I/R in vivo remain unclear. To investigate whether luteolin exerts cardioprotective effects and to monitor changes in SERCA2a expression and activity levels in vivo during I/R, we created a myocardial I/R rat model by ligating the coronary artery. We demonstrated that luteolin could reduce the myocardial infarct size, lactate dehydrogenase release, and apoptosis during I/R injury in vivo. Furthermore, we found that luteolin inhibited the I/R-induced decrease in SERCA2a activity in vivo. However, neither I/R nor luteolin altered SERCA2a expression levels in myocardiocytes. Moreover, the PI3K/Akt signaling pathway played a vital role in this mechanism. In conclusion, the present study has confirmed for the first time that luteolin yields cardioprotective effects against I/R injury by inhibiting the I/R-induced decrease in SERCA2a activity partially via the PI3K/Akt signaling pathway in vivo, independent of SERCA2a protein level regulation. SERCA2a activity presents a novel biomarker to assess the progress of I/R injury in experimental research and clinical applications.

Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice

“…Our previous studies have demonstrated that Lut can protect the myocardium from I/R injury by down-regulating microRNA-208b-3p [17] and the PI3K/Akt pathway [18]. Moreover, decreased expression and activity of SERCA2a can be partly reversed by Lut [19, 20]. These studies provide evidence that Lut has a protective effect on heart.…”

Luteolin improves cardiac dysfunction in heart failure rats by regulating sarcoplasmic reticulum Ca2+-ATPase 2a

“…Lut group were fed with Lut administration (10 ug/Kg/d, ip)48 for 14d. Lut + LY group were fed with Lut administration (10 ug/Kg/d, ip) and LY administration (0.3 mg/Kg/d, ip)19 for 14d. Lut + LY + TG group were fed with Lut administration (10 ug/Kg/d, ip) and LY administration (0.3 mg/Kg/d, ip) for 14d, and subjected to SERCA2a inhibitor TG (1 mg/kg/d, ip) on the twelfth day47.…”

“…The protein expression was examined by western blot analysis as previously described1619. Total protein was harvested from cultured cells or myocardium tissue.…”

“…Our another study showed that Lut had cardioprotection against I/R injury by improving the I/R-induced decrease in SERCA2a activity partially via the PI3K/Akt signaling pathway in vivo 19. Therefore in the present study, we expected to explore whether, and if so, how Lut enhances the contractility of failing cardiomyocytes and intact heart in rats.…”

Luteolin: A Flavonoid that Has Multiple Cardio-Protective Effects and Its Molecular Mechanisms

“…Our previous study found that Lut improved SERCA2a activity partially through activation of the PI3K/AKT signaling pathway and increased the phosphorylation of AKT (p-Akt) at amino acids 308 and 473 levels, but did not change the SERCA2a expression at protein levels. The infarct size, pro-apoptosis proteins, and lactate dehydrogenase release (LDH) release were reduced by Lut during I/R injury in vivo ( Nai et al, 2015 ), and the same effects were seen in diabetic rats ( Sun D. et al, 2012 ).…”