Folate pro-drug of cystamine as an enhanced treatment for nephropathic cystinosis.

Nephropathic cystinosis is a rare autosomal recessive disease characterised by raised intracellular levels of the amino acid, cystine. If untreated, the disease, progressively deteriorates towards end stage renal disease (ESRD) at the end of the first decade. The disease is caused by a defect in the lysosomal transport mechanism for cystine. The treatment of choice is the aminothiol cysteamine which acts as a lysine mimic. However, cysteamine possesses an offensive taste and smell and irritates the gastrointestinal tract leading to nausea and vomiting following administration. Furthermore, the rapid metabolism of cysteamine requires oral administration every 6 h for life, in consequence, the patient compliance is poor. As part of our continuing work to obtain new pro-drugs for the treatment of this genetic disease, we have synthesised a folate derivative of cystamine, the disulfide derivative of cysteamine. This new pro-drug was non cytotoxic, showed greater ability to deplete intralysosomal cystine than the current treatment, and, in fact has been the most effective reducer of intralysosomal cystine discovered in our laboratories to date.

GPR55 deletion in mice leads to age-related ventricular dysfunction and impaired adrenoceptor-mediated inotropic responses.

G protein coupled receptor 55 (GPR55) is expressed throughout the body, and although its exact physiological function is unknown, studies have suggested a role in the cardiovascular system. In particular, GPR55 has been proposed as mediating the haemodynamic effects of a number of atypical cannabinoid ligands; however this data is conflicting. Thus, given the incongruous nature of our understanding of the GPR55 receptor and the relative paucity of literature regarding its role in cardiovascular physiology, this study was carried out to examine the influence of GPR55 on cardiac function. Cardiac function was assessed via pressure volume loop analysis, and cardiac morphology/composition assessed via histological staining, in both wild-type (WT) and GPR55 knockout (GPR55(-/-)) mice. Pressure volume loop analysis revealed that basal cardiac function was similar in young WT and GPR55(-/-) mice. In contrast, mature GPR55(-/-) mice were characterised by both significant ventricular remodelling (reduced left ventricular wall thickness and increased collagen deposition) and systolic dysfunction when compared to age-matched WT mice. In particular, the load-dependent parameter, ejection fraction, and the load-independent indices, end-systolic pressure-volume relationship (ESPVR) and Emax, were all significantly (P<0.05) attenuated in mature GPR55(-/-) mice. Furthermore, GPR55(-/-) mice at all ages were characterised by a reduced contractile reserve. Our findings demonstrate that mice deficient in GPR55 exhibit maladaptive adrenergic signalling, as evidenced by the reduced contractile reserve. Furthermore, with age these mice are characterised by both significant adverse ventricular remodelling and systolic dysfunction. Taken together, this may suggest a role for GPR55 in the control of adrenergic signalling in the heart and potentially a role for this receptor in the pathogenesis of heart failure.

Quantitative measurement of mature collagen cross-links in human carotid artery plaques.

While there is an appreciable understanding of the importance of collagen breakdown in contributing to atherosclerotic plaque vulnerability and rupture, little is known about changes in collagen maturation in the atherosclerotic plaque. This is achieved through the formation of the covalent intermolecular cross-links pyridinoline (Pyd) and deoxypyridinoline (Dpd). In this study we collected carotid endarterectomy specimens from patients and undertook (i) histological assessment of collagen and inflammatory cell distribution and (ii) biochemical analysis of total collagen and cross-link content. Greater collagen deposition, increased presence of CD68 positive cells and an increased Pyd:Dpd ratio (an indicator of lysyl hydroxylase (LH-1) activity) were found in plaque versus normal vascular tissue. These findings are the first measurements of Pyd and Dpd cross-links in normal and atherosclerotic vascular tissue. The observed differences in cross-links in the plaque may adversely affect tensile strength and may have relevance to the mechanisms underlying rupture of vulnerable plaques.