Luteolin Enhances Sarcoplasmic Reticulum Ca2+-ATPase Activity through p38 MAPK Signaling thus Improving Rat Cardiac Function after Ischemia/Reperfusion

Abstract

Background/Aims: A major challenge for current therapeutic strategies against ischemia/reperfusion (I/R) is the lack of effective drugs. Considering luteolin enhances the activity of sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2a) to improve the systolic/diastolic function of rat hearts and cardiomyocytes during the I/R process, we studied the regulatory function of the p38 MAPK pathway in this protective mechanism. Methods: Isolated cardiomyocytes and perfused hearts were separately divided into five groups and used to investigate I/R. The phosphorylation of p38 and phospholamban (p-PLB), the levels and activity of SERCA2a and the levels of proteins related to apoptosis were measured. Apoptotic cells were assessed using the TUNEL assay. Single-cell shortening, Ca²⁺ transients, and the decay of the mitochondrial membrane potential (Δψm) were detected. Results: The p38 MAPK pathway was activated during the I/R process, and inhibiting it with SB203580 promoted p-PLB, which enhanced the activity of SERCA2a and relieved the calcium overload to promote the recovery of the Δψm and reduce cardiomyocyte apoptosis in I/R. Luteolin also suppressed the activation of the p38 MAPK pathway and showed cardioprotective effects during I/R injury. Conclusions: We conclude that luteolin enhances SERCA2a activity to improve systolic/diastolic function during I/R in rat hearts and cardiomyocytes by attenuating the inhibitive effects of the p38 pathway on p-PLB.

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

“…Our previous study has demonstrated that Lut can improve myocardial contractile function in I/R injury through the ERK/PP1a/PLB/SERCA2a signaling pathway [20], and enhancing SERCA2a activity by p38 MAPK Signaling [39]. In terms of transcription factors, a number of studies have provided compelling evidence that HIF-1α, SP1 and Egr-1 are involved in the regulation of SERCA2a [40-42].…”

Current Mechanistic Concepts in Ischemia and Reperfusion Injury

“…Regulatory autophagy pathways include mTOR, PI3K-Akt, p53, CA-AMPK and endoplasmic reticulum pressure (Fig. 3) [108, 109]. mTOR is located downstream of PI3K-Akt signaling, regulates cell growth, and inhibits the initial process of autophagy [110, 111].…”

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

“…Intracellular Ca 2+ handling was impaired with advanced aging. Excessive accumulated Ca 2+ in mitochondria not only leads to damage of the oxidation respiratory chain, decreased Oxidative Medicine and Cellular Longevity MB, and increased mtROS but also causes mitochondrial dysfunction, cell apoptosis, and death [96]. The p38 MAPK pathway was activated and induced calcium overload during I/R, which could be relieved by SB203580 (an inhibitor of p38 MAPK) to accelerate the recovery speed of mitochondrial biogenesis and to increase the mtDNA content [97].…”