No abstract

Luteolin has long been used in traditional Chinese medicine for treatment of various diseases. Recent studies have suggested that administration of luteolin yields cardioprotective effects during ischemia/reperfusion (I/R) in rats. However, the precise mechanisms of this action remain unclear. The aim of this study is to confirm that luteolin-mediated extracellular signal regulated kinase (ERK1/2) and c-Jun N-terminal kinase (JNK) pathways are responsible for their cardioprotective effects during I/R. Wistar rats were divided into the following groups: (i) DMSO group (DMSO); (ii) I/R group (I/R); (iii) luteolin+I/R group (Lut+I/R); (iv) ERK1/2 inhibitor PD98059+I/R group (PD+I/R); (v) PD98059+luteolin+I/R group (PD+Lut+I/R); and (vi) JNK inhibitor SP600125+I/R group (SP+I/R). The following properties were measured: contractile function of isolated heart and cardiomyocytes; infarct size; the release of lactate dehydrogenase (LDH); the percentage of apoptotic cells; the expression levels of Bcl-2 and Bax; and phosphorylation status of ERK1/2, JNK, type 1 protein phosphatase (PP1a), phospholamban (PLB) and sarcoplasmic reticulum Ca2+-ATPase (SERCA2a). Our data showed that pretreatment with luteolin or SP600125 significantly improved the contraction of the isolated heart and cardiomyocytes, reduced infarct size and LDH activity, decreased the rate of apoptosis and increased the Bcl-2/Bax ratio. However, pretreatment with PD98059 alone before I/R had no effect on the above indexes. Further, these consequences of luteolin pretreatment were abrogated by co-administration of PD98059. We also found that pretreatment with PD98059 caused a significant increase in JNK expression, and SP600125 could cause ERK1/2 activation during I/R. In addition, we are the first to demonstrate that luteolin affects PP1a expression, which results in the up-regulation of the PLB, thereby relieving its inhibition of SERCA2a. These results showed that luteolin improves cardiomyocyte contractile function after I/R injury by an ERK1/2-PP1a-PLB-SERCA2a-mediated mechanism independent of JNK signaling pathway.

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 Ca 2+ -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 Ca 2+ 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.Heart failure (HF) is a complex syndrome that results from the deterioration of the cardiac structure and function, characterized by the impaired ability of the ventricle to fill with or eject blood 1 . It is an ultimate common pathway that begins with diverse etiologies, such as hypertension, ischemia, tachycardia, infection, metabolic disorder, and cardiomyopathy, and develops with continual activation of the renin-angiotensin and sympathetic nervous systems. The incidence, prevalence and economic burden of HF are now steadily increasing due to the aging of the population and transition of acute cardiac problems into chronic disorders.Abnormality Ca 2+ homeostasis is a universal characteristic of human and experimental HF 2 . Ca 2+ homeostasis is directly modulated by four proteins: L-type Ca 2+ channel and Na + /Ca 2+ exchanger (NCX) in cell membrane, Ca 2+ -ATPase and ryanodine receptor type 2 in sarcoplasmic reticulum (SR) 3 . Any abnormality of the expression or activity of the Ca 2+ handling proteins mentioned above leads to alterations in cardiac contractility. Sarcoplasmic reticulum Ca 2+ -ATPase 2a (SERCA2a), a principal cardiac form of SERCA, is important in controlling excitation/contraction coupling. SERCA2a's role in HF has been extensively studied in animal models and human, which have shown that SERCA expression and activity are reduced in failing myocardium 4 . Genetic treatments show that reduction in SERCA2a level results in impaired intracellular Ca 2+ homeostasis and reduces both systolic and diastolic function 5,6 . These results indicate that modul...

Background Although it is accepted that the etiology of cerebral small vessel disease (CSVD) is associated with cardiovascular risk factors, the association between CSVD and the circadian rhythm of blood pressure (BP) is unclear. We aimed to determine if such an association existed in the elderly population. Method White matter hyperintensities (WMHs), lacunes, microbleeds, nocturnal dipping pattern (NDP), and morning surge in systolic blood pressure (SBP) were assessed in 2,091 participants ≥60 years of age. Results During an average of 63 months of follow-up, WMH and the WMH-to-intracranial volume ratio were significantly increased in extreme dippers, nondippers, and reverse dippers than those in dippers (p < .001). For new-incident Fazekas scale ≥2, the hazard ratios were 1.77 (95% confidence interval [CI], 1.09–2.86) for extreme dippers, 2.20 (95% CI, 1.48–3.28) for nondippers, and 2.43 (95% CI, 1.59–3.70) for reverse dippers compared with dippers, and 1.04 (95% CI, 0.81–1.35) for higher morning surge compared with lower morning surge. Nondippers and reverse dippers were associated with higher risks of new-incident lacunes and microbleeds than dippers (p < .05). Higher morning surge was associated with a higher risk of new-incident microbleeds than lower morning surge (p < .05). Conclusion NDPs in SBP played an important role in CSVD, and the morning surge in SBP was associated with cerebral microbleeds in community-based elderly population beyond the average SBP level.