Peter J. Little

Cardiovascular actions and therapeutic potential of tanshinone IIA

Tanshinone IIA (TS), a pharmacologically active component isolated from the rhizome of the Chinese herb Salvia miltiorrhiza Bunge (Danshen), has been clinically used in Asian countries for the prevention and treatment of coronary heart disease. Recently, the pharmacological properties of TS in the cardiovascular system have attracted great interest. Emerging experimental studies and clinical trials have demonstrated that TS prevents atherogenesis as well as cardiac injury and hypertrophy. In atherosclerosis, TS acts by inhibiting LDL oxidation, monocyte adhesion to endothelium, smooth muscle cell migration and proliferation, macrophage cholesterol accumulation, proinflammatory cytokine expression and platelet aggregation. TS has some activity and potential to stabilize atherosclerotic plaques. The cardioprotective effects of TS are mainly related to its anti-oxidant and anti-inflammatory actions. In this review, we focus on the protective effects and the mechanism of action of TS in the cardiovascular system, and provide a novel perspective on clinical use of TS.

Effect of moderate alcohol upon obstructive sleep apnoea

Moderate-to-large quantities of alcohol are known to aggravate severe obstructive sleep apnoea (OSA), however, the reported effects of moderate alcohol consumption upon mild-to-moderate OSA are inconsistent. Given the reported benefits of moderate alcohol consumption on cardiovascular mortality, recommendations regarding the management of patients with OSA are difficult to formulate. The aim of this study was to evaluate the effects of moderate alcohol on sleep and breathing in subjects with mild-to-moderate OSA. Twenty-one male volunteers, who snored habitually, underwent polysomnography with and without 0.5 g alcohol x kg body weight (BW)(-1) consumed 90 min prior to sleep time, in random order. The mean blood alcohol concentration (BAC) following alcohol at the time of lights out was 0.07 g x dL(-1). The distribution amongst the various sleep stages was not significantly altered by alcohol. The mean apnoea/hypopnoea index rose from 7.1+/-1.9 to 9.7+/-2.1 events x h(-1) (mean+/-SEM, p=0.017); however, there was no significant change in the minimum arterial oxygen saturation measured by pulse oximetry Sp,O2, apnoea length or snoring intensity. Mean sleep cardiac frequency rose significantly from 53.9+/-1.4 to 59.9+/-1.9 beats x min(-1) (P<0.001) and overnight urinary noradrenalin increased from 14.9+/-2.3 to 18.8+/-2.3 nmol x mmol creatinine(-1) (p=0.061) on the alcohol night compared to the nonalcohol night. To conclude, modest alcohol consumption, giving a mean blood alcohol concentration of 0.07 g x dL(-1), significantly increases both obstructive sleep apnoea frequency and mean sleep cardiac frequency.

Endothelin-1 signalling in vascular smooth muscle: Pathways controlling cellular functions associated with atherosclerosis

Atherosclerosis is the primary ischaemic vascular condition underlying a majority of cardiovascular disease related deaths. Endothelin-1 is a vasoactive peptide agent upregulated in atherosclerosis and in conjunction with its G protein-coupled receptors exerts diverse actions on all cells of the vasculature in particular vascular smooth muscle cells (VSMC). The effects of endothelin-1 include cell proliferation, migration and contraction, and the induction of extracellular matrix components and growth factors. VSMC as the major component of the neointima in atherosclerotic plaques accordingly play a key role in atherogenesis. In this review we examine classic and novel signalling pathways activated by endothelin-1 in VSMC (including phospholipase C, adenylate cyclase, Rho kinase, transactivation of receptor tyrosine kinases, mitogen activated protein kinase cascades and beta-arrestin) and their likely impact on the development and progression of atherosclerosis.

LOX-1 in atherosclerosis: biological functions and pharmacological modifiers

Lectin-like oxidized LDL (oxLDL) receptor-1 (LOX-1, also known as OLR-1), is a class E scavenger receptor that mediates the uptake of oxLDL by vascular cells. LOX-1 is involved in endothelial dysfunction, monocyte adhesion, the proliferation, migration, and apoptosis of smooth muscle cells, foam cell formation, platelet activation, as well as plaque instability; all of these events are critical in the pathogenesis of atherosclerosis. These LOX-1-dependent biological processes contribute to plaque instability and the ultimate clinical sequelae of plaque rupture and life-threatening tissue ischemia. Administration of anti-LOX-1 antibodies inhibits atherosclerosis by decreasing these cellular events. Over the past decade, multiple drugs including naturally occurring antioxidants, statins, antiinflammatory agents, antihypertensive and antihyperglycemic drugs have been demonstrated to inhibit vascular LOX-1 expression and activity. Therefore, LOX-1 represents an attractive therapeutic target for the treatment of human atherosclerotic diseases. This review aims to integrate the current understanding of LOX-1 signaling, regulation of LOX-1 by vasculoprotective drugs, and the importance of LOX-1 in the pathogenesis of atherosclerosis.

Inhibitory Activity of Clinical Thiazolidinedione Peroxisome Proliferator Activating Receptor-γ Ligands Toward Internal Mammary Artery, Radial Artery, and Saphenous Vein Smooth Muscle Cell Proliferation

Background—The proliferation of vascular smooth muscle cells (VSMCs) is a known response to arterial injury that is an important part of the process of restenosis and atherosclerosis. People with diabetes have an increased risk of cardiovascular disease resulting from accelerated coronary atherosclerosis. The newest drugs for Type 2 diabetes are thiazolidinediones, which are insulin-sensitizing peroxisome proliferator activating receptor-&ggr; (PPAR&ggr;) ligands. We investigated the antiproliferative effects of troglitazone, rosiglitazone, and pioglitazone on VSMCs derived from the three vascular beds used for coronary artery by-pass grafting: the internal mammary and radial artery and saphenous veins. Methods and Results—The three vessels yielded proliferating cells of slightly differing morphology. Inhibition of cell proliferation was assessed by cell counting and cell cycle studies by Western blotting for phosphorylated retinoblastoma protein. All three thiazolidinediones showed inhibitory potency toward cell proliferation with a potency troglitazone>rosiglitazone≈pioglitazone, and this potency profile was maintained toward the growth factor and insulin-stimulated phosphorylation of the retinoblastoma protein, which controls cell cycle progression. Conclusion—The inhibitory potency of clinical thiazolidinediones toward different vascular sources is dependent on the individual thiazolidinedione and very little on the vascular source.

Zinc and cardiovascular disease

Zinc is a vital element in maintaining the normal structure and physiology of cells. The fact that it has an important role in states of cardiovascular diseases has been studied and described by several research groups. It appears to have protective effects in coronary artery disease and cardiomyopathy. Intracellular zinc plays a critical role in the redox signaling pathway, whereby certain triggers such as ischemia and infarction lead to release of zinc from proteins and cause myocardial damage. In such states, replenishing with zinc has been shown to improve cardiac function and prevent further damage. Thus, the area of zinc homeostasis is emerging in cardiovascular disease research. The goal of this report is to review the current knowledge and suggest further avenues of research.

Regulation of glycosaminoglycan structure and atherogenesis

Cardiovascular disease is the major cause of premature death in modern society, and its impact is increasing due to rising rates of obesity and type 2diabetes. Clinical studies based on targeting metabolic abnormalities and biomarkers demonstrate significant benefits, but always an element of disease remains which is resistant to treatment. Recent evidence has strongly implicated an early interaction of atherogenic lipoproteins with vascular matrix proteoglycans as the initiating step in atherogenesis. Expert commentary has pointed to the need for vascular directed therapies to provide reductions in the residual disease component. We propose that the regulation of synthesis and thus structure of glycosaminoglycans on proteoglycans provides a potential pathway to this reduction. We review existing evidence that the vascular synthesis of glycosaminoglycan chains can be regulated in a manner which reduces lipoprotein binding and the potential application of this strategy to attenuation of the current cardiovascular disease pandemic.

Hyperelongated biglycan: the surreptitious initiator of atherosclerosis

Purpose of review To outline a role for the dermatan sulfate proteoglycan biglycan and specifically its growth factor modified form having elongated glycosaminoglycan chains as being a primary initiator of atherosclerosis. Recent findings Antiatherosclerotic therapies have mostly targeted epidemiologically identified, experimentally confirmed risk factors. The efficacy of such therapies is less than optimal, and rates of cardiovascular disease remain stubbornly high. A variety of targets have been actively pursued, but as yet no new therapy has emerged that specifically targets the vessel wall. One area concerns the role of proteoglycans in the trapping of atherogenic lipoproteins as an early and initiating step in atherogenesis. On the basis of studies in human coronary arteries, the prime proteoglycan for lipoprotein retention is biglycan. The glycosaminoglycan chains on biglycan are subject to regulation that yields several structural changes, but most prominently elongation of the chains to form ‘hyperelongated biglycan’. Multiple animal studies and a recent human disorder study have demonstrated the colocalization of atherogenic lipoproteins with biglycan in atherosclerotic lesions. Moreover, in the human atherosclerosis, the deposition of lipid appears to precede the chronic inflammatory response typical of atherosclerotic lesions. Summary The process of biglycan-associated glycosaminoglycan elongation represents a novel potential therapeutic target worthy of full investigation for the prevention of atherosclerosis.

Angiotensin II and noradrenaline increase PDGF-BB receptors and potentiate PDGF-BB stimulated DNA synthesis in vascular smooth muscle

The effects of angiotensin II and noradrenaline were examined on PDGF-BB and PDGF-AB induced mitogenesis in primary cultures of rat aortic smooth muscle. Incubation of the smooth muscle with either angiotensin II or noradrenaline potentiated the submaximal but not maximal mitogenic effects of PDGF-BB but not PDGF-AB. These effects on PDGF-BB stimulated mitogenesis correlated with an increase in receptor number specific for this homodimer when the smooth muscle was incubated with either angiotensin II or noradrenaline. Mitogenic concentrations of PDGF-AB did not interact with this PDGF receptor subtype. These results indicate that the mitogenic effects of PDGF-AB and -BB are elicited via different PDGF receptor subtypes. Angiotensin II and noradrenaline potentiate the mitogenic effects of PDGF-BB by increasing the steady state concentrations of membrane receptors for this homodimer.

Differential effects of gemfibrozil on migration, proliferation and proteoglycan production in human vascular smooth muscle cells.

The aim of this study was to determine, if gemfibrozil has anti-atherogenic actions on human vascular smooth muscle cells (SMCs) and whether these actions are affected by high glucose concentrations, which mimic the hyperglycemia of diabetes. Proliferation of SMCs treated with gemfibrozil was estimated by cell counting (Coulter Counter) and [3H]thymidine incorporation, migration in a scrape-wound assay, proteoglycan (PG) biosynthesis and glycosaminoglycan (GAG) synthesis on xyloside by [35S]sulfate labeling and sizing by sodium dodecyl sulphide-polyacrylamide gel electrophoresis (SDS-PAGE). Gemfibrozil (100 micromol/l) did not affect migration in low or high glucose media. Gemfibrozil caused concentration-dependent inhibition of proliferation in low glucose media (24% inhibition at 100 micromol/l, P<0.01) and inhibited the re-initiation of DNA synthesis by 33.3% (100 micromol/l, P<0.05) in low glucose and 31.4% (100 micromol/l, P<0.001) in high glucose conditions. In low and high glucose media, gemfibrozil (100 micromol/l) reduced total PG production in the presence of TGF-beta 1, which was associated with a decrease in the apparent size of PGs. Gemfibrozil and another PPAR-alpha ligand, WY-14643, significantly inhibited basal and TGF-beta1 stimulated GAG synthesis. We conclude that some SMCs properties associated with atherogenesis are favorably affected by gemfibrozil. Hence, direct vascular actions of gemfibrozil observed in this study may contribute to the reduction in cardiovascular disease observed in clinical studies with gemfibrozil.