Attenuation of Inflammatory Response and Reduction in Infarct Size by Postconditioning Are Associated With Downregulation of Early Growth Response 1 During Reperfusion in Rat Heart

Abstract

Early growth response 1 (EGR-1) works as a master regulator that plays a key role in triggering inflammation-induced tissue injury after ischemia and reperfusion. This study tested the hypothesis that postconditioning (Postcon) or anti-inflammatory compound, curcumin, ameliorates inflammatory responses and further reduces infarct size by normalizing EGR-1 expression during reperfusion. In the control group, male Sprague-Dawley rats were subjected to 30-min ischemia and 180-min reperfusion. Postcon with four cycles of 10-s/10-s reperfusion/ischemia was applied at the onset of reperfusion. Curcumin (150 mg/kg per day) was fed 5 days before ischemia. Relative to the control, Postcon reduced expression of EGR-1 mRNA and protein, as further identified by less EGR-1 immunoreactivity in myocardial nuclei and microvessels during reperfusion. Along with EGR-1 downregulation, levels of plasma and myocardial tumor necrosis factor α and interleukin 6 (IL-6) were significantly decreased. Upregulated P-selectin and intercellular adhesion molecule 1 mRNA and protein as well as their immunoreactivity at area at risk myocardium were significantly attenuated. Neutrophil extravasation identified by myeloperoxidase immunohistochemical staining was inhibited. Infarct size, determined with triphenyltetrazolium chloride staining, was smaller in the Postcon group than that in the control. The protection achieved with pretreatment with curcumin was comparable to the benefits gained by Postcon in all end points measured. In H9C2 rat cardiomyoblast cell line, EGR-1 siRNA downregulated hydrogen peroxide-induced EGR-1 mRNA expression and subsequently reduced tumor necrosis factor α mRNA level. These results suggest that EGR-1 seems to play a critical role in myocardial reperfusion injury because downregulation of EGR-1 either by Postcon or the use of pharmacological intervention reduces infarct size, most likely through an inhibition of inflammation-mediated processes.

High-Fiber Diet and Acetate Supplementation Change the Gut Microbiota and Prevent the Development of Hypertension and Heart Failure in Hypertensive Mice

“…Fiber and acetate improved heart and kidney function through regulation of key pathways and genes involved in cardiovascular health, including the transcription factor Egr1, a master regulator of CVD through cardiac and renal fibrosis, inflammation, and cardiac hypertrophy. [29][30][31] Fiber also downregulated the proinflammatory IL-1 cytokine signaling in the kidney. This is consistent with our fundamental hypothesis, which was based on the recent demonstration of a strong link between dietary fiber, the gut microbiota, and the pathogenesis of inflammatory diseases.…”

“…29 Particularly relevant to the present study is the role of Egr1 in cardiac hypertrophy, renal fibrosis, and inflammation. [29][30][31] A diet rich in fiber is associated with the production of substantial quantities of SCFAs such as acetate. 10 SCFAs are thought to act in the gut via metabolite-sensing receptors such as the inhibitory G-protein coupled receptor GPR43, which interacts with acetate.…”

“…28 It is interesting to note that in both the kidney and heart, fiber and acetate downregulated the gene for early growth response protein 1 (Egr1) mRNA ( Figure 6D), a master regulator of cardiovascular pathology. [29][30][31] Several of these common genes were in the same pathways, and they formed interconnected networks ( Figure the ability of fiber in the diet to reduce the incidence of inflammatory conditions such as asthma 10 and inflammatory bowel disease. 13 In our study, we did not observe any changes in cells of the immune system in the spleen (data not shown).…”

“…28 It is interesting to note that in both the kidney and heart, fiber and acetate downregulated the gene for early growth response protein 1 (Egr1) mRNA ( Figure 6D), a master regulator of cardiovascular pathology. [29][30][31] Several of these common genes were in the same pathways, and they formed interconnected networks ( Figure ure 6E) and acetate supplementation ( Figure VII in the online-only Data Supplement) upregulated several pathways acting on cell cycle, DNA replication, translation, mRNA metabolism, and respiratory electron chain. Similar to the renal transcriptome, this included the upregulation of circadian rhythm (fiber q=0.021 and acetate q<0.001) and a borderline downregulation of mitogenactivated protein kinase signaling (fiber q=0.078 and acetate q=0.086).…”

Ischemic postconditioning improves the expression of cellular membrane connexin 43 and attenuates the reperfusion injury in rat acute myocardial infarction

“…Revascularization could improve the prognosis of the patients with acute myocardial infarction (1), however, reperfusion could induce additional injury, which is sometimes extremely severe or fatal and diminishes the benefits of revascularization. Basic studies (3)(4)(5)(6) and small-sample clinical data (7,8) have verified that ischemic postconditioning (IPOC) could attenuate injury induced by ischemia/reperfusion (IR) and certain studies (8)(9)(10) have indicated that the mitochondrial K ATP (mitoK ATP ) channel plays an important role in cardioprotection effects of IPOC, but its molecular mechanisms are not completely clear thus far. Connexin 43 (Cx43; a gap junction protein located mainly in the ventricular myocardium in mammals) plays an important role in intercellular electrical conduction and cell survival, but whether the changes of membrane Cx43 are involved in IPOC-induced cardioprotective effects and the corresponding details is unclear.…”