Synthesis of the novel PARP-1 inhibitor AG-690/11026014 and its protective effects on angiotensin II-induced mouse cardiac remodeling

Abstract

We previously identified AG-690/11026014 (6014) as a novel poly(ADP-ribose) polymerase-1 (PARP-1) inhibitor that effectively prevented angiotensin II (Ang II)-induced cardiomyocyte hypertrophy. In the present study, we reported a new synthesis route for 6014, and investigated its protective effects on Ang II-induced cardiac remodeling and cardiac dysfunction and the underlying mechanisms in mice. We designed a new synthesis route to obtain a sufficient quantity of 6014 for this in vivo study. C57BL/6J mice were infused with Ang II and treated with 6014 (10, 30, 90 mg·kg·d, ig) for 4 weeks. Then two-dimensional echocardiography was performed to assess the cardiac function and structure. Histological changes of the hearts were examined with HE staining and Masson's trichrome staining. The protein expression was evaluated by Western blot, immunohistochemistry and immunofluorescence assays. The activities of sirtuin-1 (SIRT-1) and the content of NAD+ were detected with the corresponding test kits. Treatment with 6014 dose-dependently improved cardiac function, including LVEF, CO and SV and reversed the changes of cardiac structure in Ang II-infused mice: it significantly ameliorated Ang II-induced cardiac hypertrophy evidenced by attenuating the enlargement of cardiomyocytes, decreased HW/BW and LVW/BW, and decreased expression of hypertrophic markers ANF, BNP and β-MHC; it also prevented Ang II-induced cardiac fibrosis, as implied by the decrease in excess accumulation of extracellular matrix (ECM) components collagen I, collagen III and FN. Further studies revealed that treatment with 6014 did not affect the expression levels of PARP-1, but dose-dependently inhibited the activity of PARP-1 and subsequently restored the activity of SIRT-1 in heart tissues due to the decreased consumption of NAD+ and attenuated Poly-ADP-ribosylation (PARylation) of SIRT-1. In conclusion, the novel PARP-1 inhibitor 6014 effectively protects mice against AngII-induced cardiac remodeling and improves cardiac function. Thus, 6014 might be a potential therapeutic agent for heart diseases..

PARP1 interacts with HMGB1 and promotes its nuclear export in pathological myocardial hypertrophy

“…For PARP1, its total protein levels or subcellular localization was unaltered, but its catalytic activity, as determined by the PAR level, was remarkably enhanced after three stimulants treatment (Fig. 1g), which was consistent with our previous reports [24,25]. Upon Ang II, PE, or ISO exposure, total intracellular HMGB1 protein expression remained unchanged (Fig.…”

“…Previous study manifests that PARP −/− mice are protected against angiotensin II (Ang II)-stressed cardiac hypertrophy [23]. We reported that PARP1 is strongly activated by Ang II or isoproterenol (ISO), the PARylation of FoxO3 induced by PARP1 facilitates its phosphorylation at critical sites, leading to its translocation from the nucleus and finally resulting in cardiac hypertrophy [24,25]. In addition, it was reported that PARP modified HMGB1 in vitro and influenced its subcellular relocalization during necrosis process [26].…”

SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection

“…However, research on sirtuinmodulating compounds is still intensive, and specific hydrophobic motifs found in SIRT1 substrates, such as FOXO3a and PGC-1a, seem to facilitate SIRT1 activation by sirtuinactivating compounds (STACs) acting through a mechanism of direct ''assisted allosteric activation'' mediated by an N-terminal activation domain in SIRT1 (74,75,148). Moreover, recently, a synthetic sulfonylurea compound (G004) showed beneficial effects on ApoE -/-mice against hyperglycemia and atherosclerosis by acting on SIRT1/ eNOS axis (149), and a novel PARP1 inhibitor AG-690/ 11026014 showed protective effects on Ang II-induced mouse cardiac remodeling by restoring the activity of SIRT1 in heart tissues (54).…”

Poly(ADP‐ribose) polymerase 1 induces cardiac fibrosis by mediating mammalian target of rapamycin activity

“…22,23 The depletion of intracellular NAD, on the one hand, rapidly results in the decline in the level of adenosine triphosphate, which is involved in energy metabolism 24 ; on the other hand, depletion leads to decay of class-Ⅲ histone deacetylases sirtuins catalytic activity. [26][27][28][29][30][31] For instance, PARP −/− mice are protected against angiotensin Ⅱ (AngⅡ)-mediated myocardial hypertrophy accompanied by NAD repletion and sirtuins inactivation. [26][27][28][29][30][31] For instance, PARP −/− mice are protected against angiotensin Ⅱ (AngⅡ)-mediated myocardial hypertrophy accompanied by NAD repletion and sirtuins inactivation.…”

“…[26][27][28][29][30][31] For instance, PARP −/− mice are protected against angiotensin Ⅱ (AngⅡ)-mediated myocardial hypertrophy accompanied by NAD repletion and sirtuins inactivation. [26][27][28]30,31 Recently, we reported that the PARylation of FoxO3 induced by PARP1 facilitates its phosphorylation at critical sites, leading to its translocation from the nucleus and finally resulting in cardiac hypertrophy. [26][27][28]30,31 Recently, we reported that the PARylation of FoxO3 induced by PARP1 facilitates its phosphorylation at critical sites, leading to its translocation from the nucleus and finally resulting in cardiac hypertrophy.…”