Possibility of Inhibition of TNF-α/NF-kB Signaling Pathway Activation in Myocardium and Reverse Cardiac Hemodynamics in Chronic Ischemic Heart Disease

Abstract

Introduction: Chronic ischemic heart disease (CIHD) caused by long term aortic stenosis characterizes the refractory to the conventional therapy. We investigated whether the restoration of redox-potential in myocardium prevents the progression of the symptoms of congestive heart failure (CHF) and myocardial inflammation in rabbits. Material and Methods: 8 weeks after induction of CIHD by left descending coronary artery stenosis all animals were randomly assigned into 3 groups: control II - without therapy (infusion of 0,9% NaCl); main I - animals received 5,0 mg/kg Lisinopril and metoprolol, 1 mg/kg body weight administrated in drinking water and furosemide 1.0 mg/kg i.v. (bolus) once daily and main II received 10 mg/kg of Adenocin dissolved in water for injection i.v, once daily. The control I group included sham operated animals and infusion of 0.9% NaCl. All animals were euthanized throughout 14 days after beginning of treatment. Results: Long-term aortic stenosis has led to a simultaneously developing of CHF, diagnosed by developing cardiac hypertrophy, increased level of brain natriuretic peptide (BNP) and myocardial oedema. Treatment with Adenocin® significantly improved cardiac hemodynamics, decreased water content in myocardium and BNP in plasma, decreased the content of proinflammatory cytokines and unlike treatment with furosemide, lisinopril and metoprolol, increased level of anti-inflammatory interleukin-10. Restoration of myocardium redox-potential and level of NAD under treatment with Adenocin® led to decreasing the activity of nuclear transcription factor kappa B (NF-kB) and production of vasoconstrictor component of endothelial system, endothelin-1 in myocardium. Potential important link between cellular metabolism (hypoxia/ischemia) and innate inflammatory system homeostasis is the level of redox-potential, NAD/NADH in myocardium. Conclusion: Influence of first oxidized form of NAD-containing positive inotropic drug Adenocin® leads to the decreasing symptoms of CHF and occurs beneficial action on the balance between pro- and anti-inflammatory cytokines in myocardium and activity of NF-kB.