Novel targets for the treatment of heart failure accompanied with systemic inflammatory response syndrome in experiments.

D.Iu. Ionov, P.A. Galenko-Iaroshevsky, G.V. Sukoyan, N.M. Dolidze. 1Kuban State Medical University, Pharmacology, 350063, Russia, 2Kuban State Medical University, Pharmacology, 350063, Russia, 3Scientific Research Institute of General Pathology and Pathophysiology, Bioenergetics, 125315, Russia, 4Scientific Research Institute of General Pathology and Pathophysiology, Bioenergetics, 125315, Russia

In recent years, new potential therapeutic targets that are involved in the pathogenesis of congestive heart failure (CHF) have been identified, and new drugs are currently under investigation. A repeated finding is that the positive results that have been observed in preclinical studies and Phase II trials are not always confirmed in Phase III studies. This work analyses the new therapeutic targets (for example, ventricular remodelling, cytokines profile, system of NAD-dependent enzymes, such as sirtuins (SIRT) and poly(ADP-ribose) polymerase-1 (PARP), a chromatin-bound enzyme activation. Sirtuins (SIRT) post-translationally modulate the function of many cellular proteins that undergo reversible acetylation-deacetylation cycles, affecting physiological responses that have implications for treating diseases. Potent small-molecule modulators of SIRTs have shown efficacy in preclinical models of metabolic, neurodegenerative and inflammatory diseases, and so hold promise for drug discovery efforts in multiple therapeutic areas. Since the discovery of NAD-dependent deacetylases, Sirtuins, it has been recognized that maintaining intracellular levels of NAD is crucial for the management of stress-response of cells. Here we show that chronic inflammatory disease such as congestive heart failure, caused by toxi-allergic myocarditis (TAM) 10-day duration induced cardiac hypertrophy is associated with loss of intracellular levels of NAD. Afterwards, redox-potential NAD(+)/NADH and enzyme activity of SIRT, poly(ADP-ribose) polymerase-1 (PARP) and cytokine profile was determined. It was shown, that in TAM 10-day duration the content of NAD decrease more than 70% and ration of NAD(+)/NADH from 1,2±0,1 to 0,56±0,03. Treatment of TAM with adenocin as a NAD-containing drug, during 5-days induced the NAD(+)/NADH ratio increasing and the levels of SIRT1 and SIRT3 activity decreasing as well as cardiac hypertrophy blocking in vitro. Activating SIRT by NAD blocked the activation of pro-hypertrophic proteinkinase B (Akt) signaling. This also accompanied with positive action of adenocin on the ratio between pro- and anti-inflammatory cytokine production and endotoxemia as a whole. Modulation of the activity of PARP contributing to cardiac hypertrophy indicating that treatment of adenocin and subsequent restoration of NAD pools are the sequence of events causing angiotensin II-mediated cardiomyocyte cell death cessation. We also show that NAD depletion, which results from PARP overactivation, contributes to angiotensin II-mediated cardiac myocyte cell death. This type of cell death was prevented by NAD repletion and activation of the longevity factor Sir2α. These results demonstrate that PARP is a downstream nuclear target of angiotensin II-induced signaling pathway, contributing to cardiac hypertrophy and failure. These results reveal a novel role of NAD and more pronounced of adenocin as an inhibitor of cardiac hypertrophic signaling, and suggest that only prevention of NAD depletion may be critical in the treatment of cardiac hypertrophy, caused by noncoronarogenic disease. Any other selective development new medicines targeting to inhibition of PARP-activities of modulation of SIRT activity or anticytokine drug even it some positive results that have been observed in preclinical studies did not be efficacy in multiple disease and syndromes such as chronic stable angina, chronic heart failure, diabetes mellitus, systemic inflammatory response syndrome.