Methylated arginine analogues: their potential role in atherosclerosis and cognition using the poloxamer-407-induced mouse model of dyslipidemia.

An experimental mouse model of dyslipidemia and atherosclerosis was utilized to study the generation of methylarginines in vivo, as well as any potential behavioral changes in mice associated with the production of excess methylarginines. Following 14 weeks of poloxamer 407 treatment, mice developed atherosclerosis and the plasma concentrations of monomethylarginine and asymmetric dimethylarginine were found to be significantly greater than corresponding concentrations in control mice. This finding may have contributed to the development of aortic atherosclerotic lesions in poloxamer-treated mice by interfering with nitric oxide availability and, hence, normal function of vascular endothelium. Poloxamer-407-treated mice also showed a significant decrease in locomotor and exploratory activity, together with signs of emotional stress and anxiety relative to controls. Passive avoidance testing to assess learning and memory provided suggestive evidence that poloxamer-treated mice could potentially be characterized as having undergone a disruption in the process of forgetting about an aversive event, specifically, a foot shock, when compared with control mice. Thus, it is also suggested that the increase in both plasma monomethylarginine and asymmetric dimethylarginine in poloxamer-407-treated mice may somehow influence learning and memory, because endothelial dysfunction caused by reduced nitric oxide availability has been hypothesized to negatively influence cognitive function.

The influence of acute renal injury on arginine and methylarginines metabolism.

Arginine (ARG) and its methylated analogs (methylarginines) are the crucial regulators of nitric oxide (NO) bioavailability. ARG is the substrate for NO synthesis, whereas monomethylarginine (MMA) and asymmetric dimethylarginine (ADMA) are potent inhibitors. Symmetric dimethylarginine (SDMA) does not interfere with NO synthesis, but competes with ARG for the intracellular transport. The kidneys play the major role in ARG and methylarginines metabolism. They synthesize ARG de novo and eliminate methylarginines by excretion into urine and also by enzyme dimethylarginine dimethylaminohydrolase (DDAH) degrading only ADMA and MMA. Acute renal injury (ARI) is known to be accompanied by reduced NO production in the body. This study aimed to investigate the influence of ARI on ARG and methylarginines metabolism, and to establish the relationship between disturbances in the latter and reduced NO bioavailability in ARI. The rhabdomyolysis-related ARI model in rats was used. ARI reduced renal synthesis of ARG and its level in circulation as well as renal DDAH activity. However, ADMA did not accumulate because of its increased urinary excretion. Whole-body production of SDMA was increased significantly, whereas whole-body metabolism of MMA did not change. ARG and methylarginines content in renal tissue was decreased. Moreover, the balance between the substrate and inhibitors for NO synthesis was changed in favor of the inhibitors in renal tissue as well as in blood, and daily urinary excretion of NO metabolites was significantly decreased. Thus, ARI provokes severe disturbances in ARG and methylarginines metabolism that results in reduced NO bioavailability in the kidney and the whole body.

How May Proton Pump Inhibitors Impair Cardiovascular Health?

Proton pump inhibitors (PPIs) are among the most widely used drugs worldwide. They are used to treat a number of gastroesophageal disorders and are usually prescribed as a long-term medication or even taken without a prescription. There are a number of clinical studies that associate PPI use with an increased cardiovascular risk. In this article, we review the clinical evidence for adverse cardiovascular effects of PPIs, and we discuss possible biological mechanisms by which PPIs can impair cardiovascular health.

Local Inhibition of Macrophage and Smooth Muscle Cell Proliferation to Suppress Plaque Progression.

Atherosclerosis is a complex process responsible for a major burden of cardiovascular morbidity and mortality. Macrophages and smooth muscle cells (SMCs) are abundant within atherosclerotic plaques. This review discusses the role of macrophages and SMCs in plaque progression and provides an overview of nanoparticle-based approaches and other current methods for local targeting of atherosclerotic plaques.

Endothelium-Derived Nitric Oxide as an Antiatherogenic Mechanism: Implications for Therapy.

Endothelium-derived nitric oxide (eNO) is a multifunctional signaling molecule critically involved in the maintenance of metabolic and cardiovascular homeostasis. In addition to its role as a potent endogenous vasodilator, eNO suppresses key processes in vascular lesion formation and opposes atherogenesis. This review discusses eNO as an antiatherogenic molecule and highlights factors that influence its bioavailability and therapeutic approaches to restore or enhance its levels.