Abstract
We previously found that luteolin (Lut) appeared to improve the contractility of cardiomyocytes during ischemia/reperfusion in rats. The enhancement was associated with the alteration in sarcoplasmic reticulum Ca2+-ATPase 2a (SERCA2a). This finding prompted us to consider if the mechanism worked in heart failure (HF). We studied the regulation of SERCA2a by Lut in failing cardiomyocytes and intact heart of rats. Improvement of contractility and the mechanisms centered on SERCA2a were studied in isolated cardiomyocytes and intact heart. We found that Lut significantly improved contractility and Ca2+ transients, ameliorated expression, activity and stability of SERCA2a and upregulated expression of small ubiquitin-related modifier (SUMO) 1, which is a newfound SERCA2a regulator. Lut also increased phosphorylation of protein kinase B (Akt), phospholaban (PLB) and sumoylation of SERCA2a, specificity protein 1 (Sp1). Transcriptions of SUMO1 and SERCA2a were concurrently increased. Inhibition of posphatidylinositol 3 kinase/Akt (PI3K/Akt) pathway and SERCA2a activity both markedly abolished Lut-induced benefits in vitro and in vivo. Lut upregulated the expression ratio of Bcl-2/Bax, caspase-3/cleaved-Caspase3. Meanwhile, Lut ameliorated the myocardium fibrosis of HF. These discoveries provide an important potential therapeutic strategy that Lut targeted SERCA2a SUMOylation related to PI3K/Akt-mediated regulations on rescuing the dysfunction of HF.
Highlights
Abnormality Ca2+ homeostasis is a universal characteristic of human and experimental HF2
Among the 17 died AAC rats, 8 died in the first four weeks, none died in the second four weeks, and 9 died in the last four weeks. It was discovered by anatomy of the dead rats that the main cause of the 8 death in the first four weeks was acute Heart failure (HF)
We found that sumoylation of Sp1 increased, and might contribute to the improvement of SERCA2a transcription
Summary
Abnormality Ca2+ homeostasis is a universal characteristic of human and experimental HF2. Any abnormality of the expression or activity of the Ca2+ handling proteins mentioned above leads to alterations in cardiac contractility. Genetic treatments show that reduction in SERCA2a level results in impaired intracellular Ca2+ homeostasis and reduces both systolic and diastolic function[5,6]. These results indicate that modulation of SERCA2a is a possible means of regulating cardiomyocytes contractility in HF. Kho et al showed that sumoylation was a critical post-translational modification in regulating SERCA2a function[10]. By means of gene therapy, they proved that sumoylation increased the intrinsic activity of SERCA2a ATPase in failing cardiomyocytes, as well as prolonging the life time of SERCA2a. Our previous study confirmed that Lut could decrease serum BNP level and partially reverse ventricular remodeling, improve cardiac function of HF rats[15]
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