Animal models to study pathogenesis and treatments of cardiac disorders in rheumatoid arthritis: Advances and challenges for clinical translation.

Although cardiac diseases such as acute myocardial infarction, heart failure and arrhythmias are the leading cause of cardiovascular complications in rheumatoid arthritis (RA), their pathogenesis is far from being understood and optimal therapeutic options to treat specifically these disorders in RA are lacking. Preclinical studies on animal models of arthritis can help to decipher the complex link between arthritis and the heart, and to identify critical pathways and novel therapeutic targets. This review presented the available data on cardiac disorders in animal models of RA, as well as the current knowledge on pathophysiology and pharmacology of these disorders. Future directions for translational studies in a cardiorheumatic perspective are proposed.

Discrepancy between in vitro and in vivo antitumor effect of a new platinum(II) metallointercalator.

Platinum(II) metallointercalators represent a new class of DNA-damaging antitumor complexes active in cisplatin- and oxaliplatin-resistant cell lines. In the first part of our work, we have screened in vitro a serie of 18 metallointercalators with the structure [Pt(A(L))(I(L))](2+) where A(L) = ethylenediamine (EN) or diaminocyclohexane in R,R- (RR) or S,S- (SS) configuration ; and I(L) = 1,10-phenanthroline with different degree of methylation : no methylation (PHEN), mono-methylated in position 4 (4ME) or 5 (5ME), or di-methylated in positions 4 and 7 (47ME) or in positions 5 and 6 (56ME) or tetramethylated in positions 3,4,7 and 8 (3478ME). Eight compounds: PHENEN, 56MEEN, 47MERR, 56MERR, 4MESS, 5MESS, 47MESS and 56MESS exhibited significant cytotoxic effect, equivalent or higher than cisplatin, oxaliplatin or carboplatin in the human HCT8 colon and IGROV1 ovarian cancer cell lines for both 1 and 24 h incubation time. The high cytotoxicity of the most active compound, the 56MESS, could be related to the hydrophobicity of the phenanthroline ligand that increases cellular uptake in human HCT8, HT29 (colon) and IGROV1 (ovarian) as well as in rat PROb colon cell lines. Unfortunately, intravenous or intraperitoneal administration of 56MESS had no antitumoral activity in BD-IX rats with peritoneal carcinomatosis induced by an intraperitoneal PROb cells inoculation. Moreover, 56MESS displayed nephrotoxicity at pharmacological dose. Thus, these data query the in vivo/in vitro correlation and reconsider the place of the in vivo screening to select adequate candidate drug for further preclinical and clinical developments.

Adjuvant-induced arthritis is a relevant model to mimic coronary and myocardial impairments in rheumatoid arthritis.

OBJECTIVES: To determine if the adjuvant-induced arthritis model reproduced coronary and cardiac impairments observed in rheumatoid arthritis patients. The link between disease activity and circulating levels of angiotensin II and endothelin-1 have been studied, as well as the myocardial susceptibility to ischemia. METHODS: At the acute inflammatory phase, coronary reactivity was assessed in isolated arteries, and cardiac function was studied in isolated perfused hearts, before and after global ischemia/reperfusion. Ischemic insult was evaluated by the infarct size, lactate dehydrogenase and creatine phosphokinase levels in coronary effluents. Cardiac myeloperoxidase activity was measured, as well as angiotensin II and endothelin-1 levels. RESULTS: Compared to controls, adjuvant-induced arthritis had reduced coronary Acetylcholine-induced relaxation associated with cardiac hypertrophy, both being correlated with plasma levels of endothelin-1 and angiotensin II, and arthritis score. Although cardiac function at baseline was similar from controls, adjuvant-induced arthritis rats exhibited lower cardiac functional recovery, increased myeloperoxidase activity, higher infarct size and creatine phosphokinase levels after ischemia/reperfusion. CONCLUSIONS: The adjuvant-induced arthritis model displays coronary endothelial dysfunction associated with myocardial hypertrophy and a reduced tolerance to ischemia. This model might be useful for deciphering the pathophysiology of cardiac dysfunction in rheumatoid arthritis and paves the way for studying the role of endothelin-1 and angiotensin II.

The role of arginase in aging: A systematic review.

Aging is a normal, progressive and multi-step degeneration in the physiological functions and metabolic processes of living organisms until death. It represents the main risk factor for many diseases (e.g. cancer, cardiovascular and neurodegenerative diseases) and contributes to increase in mortality. Aging results, at least partially, from an accumulation of cell and tissue damage related to inherited and environmental factors, leading to biological and biochemical dysregulations. Arginase is a ubiquitous L-arginine-metabolizing enzyme involved in some fundamental mechanisms such as the urea cycle or polyamines synthesis. There is a growing awareness that arginase activity and/or expression are disturbed in a tissue-dependent manner during aging. However, whether these effects on arginase pathway are a primary cause or merely a consequence of aging is still an open question. In this review dealing with the interplay between the arginase pathway and aging, we will explore the involvement of arginase in aging mechanisms and, reversely, the impact of aging on the arginase pathway in various tissues and cells. Finally, the potential interest of arginase inhibition in aging and age-related diseases will also be analyzed.

Pristane-induced arthritis in dark Agouti rat is a relevant model for mimicking vascular dysfunction and lipid paradox in rheumatoid arthritis.

OBJECTIVES: To understand the pathophysiology of cardiovascular (CV) dysfunction in rheumatoid arthritis (RA) is crucial, but limited by the paucity of animal models able to mimic CV impairments. We wanted to determine if the rat model of Pristane-Induced Arthritis (PIA) reproduced cardiometabolic impairments of RA. METHODS: Dark Agouti rats received an injection of pristane or saline (controls) at day 0. Reactivity to vasoconstrictors and vasodilators was studied in aortic rings and mesenteric arteries at day 28 (acute) and day 120 post-induction (chronic phase). Circulating markers of inflammation, lipid and glucose levels, arthritis and radiographic scores were assessed. RESULTS: In aortic rings, PIA induced a reduced vasoconstriction to phenylephrine and serotonin in both phases of the model. The relaxant effect of acetylcholine was decreased in PIA in acute (P < 0.05) but not in chronic phase. In mesenteric arteries, only the acetylcholine-induced vasorelaxation was impaired in PIA rats in the chronic phase (P < 0.001). Serum interleukin-6 levels were higher, total cholesterol and triglycerides levels were lower in PIA in both phases (P < 0.001) whereas myeloperoxidase activity and blood glucose were unchanged. Adiponectine levels were lower in PIA in acute (P < 0.001) but not in chronic phase. Endothelial function correlated with interleukin-6, total cholesterol levels and arthritis score in aorta but not in mesenteric arteries. CONCLUSIONS: As new information, PIA induces endothelial dysfunction in micro-/macro-vascular beds and low lipid levels, like in RA. This model of chronic arthritis might be useful to study CV pathophysiology and to screen new therapeutic options for reducing CV risk in RA.

[Immunosuppressive drugs and highly active antiretroviral therapy: pharmacokinetic interactions]. / Médicaments immunosuppresseurs et antirétroviraux: une association riche en interactions.

The development of highly active antiretroviral therapy has greatly improved HIV-infected patient survival. However, the increased life expectancy associated with the management of opportunistic infections might favour the onset of severe organic failure that could require organ transplantation. The use of immunosuppressive drugs in association with antiretroviral therapy will generate pharmacodynamic and pharmacokinetic interactions. In this context, therapeutic drug monitoring is of great importance to improve therapeutic management of patients.

Effects of a chronic l-arginine supplementation on the arginase pathway in aged rats.

While ageing is frequently associated with l-arginine deficiency, clinical and experimental studies provided controversial data on the interest of a chronic l-arginine supplementation with beneficial, no or even deleterious effects. It was hypothesized that these discrepancies might relate to a deviation of l-arginine metabolism towards production of l-ornithine rather than nitric oxide as a result of age-induced increase in arginase activity. This study investigated the effect of ageing on arginase activity/expression in target tissues and determined whether l-arginine supplementation modulated the effect of ageing on arginase activity. Arginase activity and expression were measured in the heart, vessel, brain, lung, kidney and liver in young rats (3-months old) and aged Wistar rats (22-24-months-old) with or without l-arginine supplementation (2.25% in drinking water for 6weeks). Plasma levels of l-arginine and l-ornithine were quantified in order to calculate the plasma l-arginine/l-ornithine ratio, considered as a reflection of arginase activity. Cardiovascular parameters (blood pressure, heart rate) and aortic vascular reactivity were also studied. Ageing dramatically reduced plasma l-arginine and l-arginine/l-ornithine ratio, decreased liver and kidney arginase activities but did not change activities in other tissues. l-Arginine supplementation normalized plasma l-arginine and l-arginine/l-ornithine ratio, improved endothelial function and decreased systolic blood pressure. These effects were associated with decreased arginase activity in aorta along with no change in the other tissues except in the lung in which activity was increased. A strong mismatch was therefore observed between arginase activity and expression in analyzed tissues. The present study reveals that ageing selectively changes arginase activity in clearance tissues, but does not support a role of the arginase pathway in the potential deleterious effect of the l-arginine supplementation in aged patients. Moreover, our data argue against the use of the measurement of plasma l-arginine/l-ornithine ratio to estimate arginase activity in aged patients.

Local cryotherapy improves adjuvant-induced arthritis through down-regulation of IL-6 / IL-17 pathway but independently of TNFα.

OBJECTIVES: Local cryotherapy is widely and empirically used in the adjuvant setting in rheumatoid arthritis treatment, however its own therapeutic and anti-inflammatory effects are poorly characterized. We aimed to evaluate the effects of local cryotherapy on local and systemic inflammation in Adjuvant-induced arthritis, a murine model of rheumatoid arthritis. METHODS: The effects of mild hypothermia (30°C for 2 hours) on cytokine protein levels (Multiplex/ELISA) were evaluated in vitro in cultured rat adjuvant-induced arthritis patellae. In vivo, local cryotherapy was applied twice a day for 14 days in arthritic rats (ice: n = 10, cold gas: n = 9, non-treated: n = 10). At day 24 after the induction of arthritis, cytokine expression levels were measured in grinded hind paws (Q-RT-PCR) and in the plasma (Multiplex/ELISA). RESULTS: In vitro, punctual mild hypothermia down-regulated IL-6 protein expression. In vivo, ice showed a better efficacy profile on the arthritis score and joint swelling and was better tolerated, while cold gas induced a biphasic response profile with initial, transient arthritis worsening. Local cryotherapy also exerted local and systemic anti-inflammatory effects, both at the gene and the protein levels: IL-6, IL-17A and IL-1ß gene expression levels were significantly down-regulated in hind paws. Both techniques decreased plasma IL-17A while ice decreased plasma IL-6 protein levels. By contrast, we observed no effect on local/systemic TNF-α pathway. CONCLUSIONS: We demonstrated for the first time that sub-chronically applied local cryotherapy (ice and cold gas) is an effective and well-tolerated treatment in adjuvant-induced arthritis. Furthermore, we provided novel insights into the cytokine pathways involved in Local cryotherapy's local and systemic anti-inflammatory effects, which were mainly IL-6/IL-17A-driven and TNF-α independent in this model.

cis-Dichloroplatinum(II) complexes tethered to dibenzo[c,h][1,6]naphthyridin-6-ones: synthesis and cytotoxicity in human cancer cell lines in vitro.

A novel family of cisplatin-type complexes tethered to dibenzo[c,h][1,6]naphthyridin-6-one topoisomerase inhibitor via a polymethylene chain and their nonplatinated counterparts were prepared. Their potential cytotoxicity was assessed in three human colorectal cancer cell lines HCT 116, SW480 and HT-29 and compared to the reference molecules cisplatin and oxaliplatin. Platinated compounds were poorly active whilst nonplatinated dibenzo[c,h][1,6]naphthyridin-6-one moieties exhibited higher cytotoxic properties than cisplatin and oxaliplatin whatever the length of the polymethylene chain; molecules containing the tri- and hexamethylene chain length were the most cytotoxic.

Synthesis, cytotoxicity and structure-activity relationships between ester and amide functionalities in novel acridine-based platinum(II) complexes.

In order to improve the pharmacological profile of the anticancer drug cisplatin, several new acridine-based tethered (ethane-1,2-diamine)platinum(II) complexes connected by a polymethylene chain were synthetized. Activity-structure relationship between amide or ester functionalities was explored by changing acridine-9-carboxamide into acridine-9-carboxylate chromophore. The in vitro cytotoxicity of these new complexes was assessed in human colic HCT 116, SW480 and HT-29 cancer cell lines. Series of complexes bearing the acridine-9-carboxylate chromophore displayed higher cytotoxic effect than acridine-9-carboxamide complexes, with gradual effect according to the size of the polymethylene linker.