Chymase: a new pharmacologic target in cardiovascular disease

Chymase is a chymotrypsin-like serine protease stored as an inactive enzyme within the secretory granules of mast cells. An important action of chymase is the angiotensin-converting enzyme (ACE)-independent synthesis of angiotensin II, which occurs immediately after its release into the interstitial tissues after vascular injury. Under physiological conditions, the role of chymase is uncertain, but under pathologic situations, chymase may have an important role. Pharmacologic strategies that serve to inhibit chymase function may prove to be useful in the setting of vascular injury.     

Endothelin as a therapeutic target in the treatment of cardiovascular disease

Endothelins, a family of peptides derived from the vascular endothelium and smooth muscle cells possess vasoconstrictor and mitogenic properties. By acting predominantly in a paracrine fashion, these peptides activate specific receptors and have protean effects in normal and diseased organ systems. The wide distribution of these receptors in various tissues mediate the multiplicity of physiologic actions attributed to endothelins. Much of our understanding about endothelins has come from the development of an array of receptor-specific and mixed receptor antagonists. Based on the promising results from animal studies, active research and drug development programs are under way to investigate the clinical potential of endothelin antagonism for treatment of cardiovascular disease.     

线粒体相关内质网膜:心血管疾病治疗的新靶点

线粒体相关内质网膜是指内质网和线粒体之间高度动态的紧密连接部分,参与维持内质网和线粒体的正常功能,与细胞脂质代谢、钙稳态、线粒体动力学、自噬和凋亡、内质网应激和炎症等密切相关。研究显示线粒体相关内质网膜功能异常或者数量和结构改变参与心血管疾病的发生发展。本文总结了线粒体相关内质网膜的功能,阐述了其在心血管疾病中的作用及可能机制,为线粒体相关内质网膜成为心血管疾病治疗的新靶点提供理论参考。     

整合素的作用及其应用:心血管疾病治疗新靶点

整合素家族受体是细胞表面重要的黏附分子,在细胞和微环境之间的相互作用中发挥着重要作用.整合素与多种人类疾病密切相关,如心血管疾病、血栓症、炎症、癌症等.是重要的药物靶点.本文主要论述整合素在心血管疾病中的研究进展.     

CD47: a new target in cardiovascular therapy

CD47, originally named integrin-associated protein, is a receptor for thrombospondin-1. A number of important roles for CD47 have been defined in regulating the migration, proliferation, and survival of vascular cells, and in regulation of innate and adaptive immunity. The recent discovery that thrombospondin-1 acts via CD47 to inhibit nitric oxide signaling throughout the vascular system has given new importance and perhaps a unifying mechanism of action to these enigmatic proteins. Here we trace the development of this exciting new paradigm for CD47 function in vascular physiology.     

Urotensin II and cardiomyopathy in end-stage renal disease

Circulating urotensin (UTN) is increased in patients with heart failure and in patients with renal diseases, and UTN antagonism is currently considered as a potential treatment for these conditions. Contrary to this contention, studies in end-stage renal disease suggest that, perhaps because of interference with sympathetic and NO systems, UTN may be cardioprotective. Therefore, we investigated the relationship between circulating UTN and echocardiographic parameters of left ventricular function (midwall fractional shortening), left atrial volume, and myocardial geometry (mean wall thickness and relative wall thickness) in 191 patients with end-stage renal disease. UTN was associated directly (r=0.39; P<0.001) with left ventricular systolic function and inversely with left atrial volume (r=-0.40; P<0.001) and the muscular component of the left ventricular (UTN versus mean wall thickness: r=-0.30, P<0.001; UTN versus relative wall thickness: r=-0.32, P<0.001). Adjustment for a series of 11 risk factors produced a relatively small change in the strength of these relationships. However, further adjustment for plasma norepinephrine or, particularly so, for the endogenous inhibitor of NO synthase asymmetrical dimethyl arginine produced a 33% to 50% decrease in the strength of such associations. Of note, there was a strong UTN-asymmetrical dimethyl arginine interaction in determining midwall fractional shortening (P=0.001) and mean wall thickness (P=0.006). These data support the hypothesis that high UTN is cardioprotective in end-stage renal disease and that interference by UTN with sympathetic activity and NO synthesis represents an intermediate mechanism mediating the favorable echocardiographic profile of patients with high UTN. Additional mechanistic insights may be needed before launching long-term clinical trials with UTN antagonists in patients with end-stage renal disease.     

Urotensin II levels in patients with inflammatory bowel disease

BACKGROUNDPatients with inflammatory bowel disease (IBD) are associated with increased cardiovascular risk and have increased overall cardiovascular burden. On the other hand, urotensin II (UII) is one of the most potent vascular constrictors with immunomodulatory effect that is connected with a number of different cardiometabolic disorders as well. Furthermore, patients with ulcerative colitis have shown increased expression of urotensin II receptor in comparison to healthy controls. Since the features of IBD includes chronic inflammation and endothelial dysfunction as well, it is plausible to assume that there is connection between increased cardiac risk in IBD and UII.AIMTo determine serum UII levels in patients with IBD and to compare them to control subjects, as well as investigate possible associations with relevant clinical and biochemical parameters.METHODSThis cross sectional study consecutively enrolled 50 adult IBD patients (26 with Crohn’s disease and 24 with ulcerative colitis) and 50 age and gender matched controls. Clinical assessment was performed by the same experienced gastroenterologist according to the latest guidelines. Ulcerative Colitis Endoscopic Index of Severity and Simple Endoscopic Score for Crohn’s Disease were used for endoscopic evaluation. Serum levels of UII were determined using the enzyme immunoassay kit for human UII, according to the manufacturer’s instructions.RESULTSIBD patients have significantly higher concentrations of UII when compared to control subjects (7.57 ± 1.41 vs 1.98 ± 0.69 ng/mL, P < 0.001), while there were no significant differences between Crohn’s disease and ulcerative colitis patients (7.49 ± 1.42 vs 7.65 ± 1.41 ng/mL, P = 0.689). There was a significant positive correlation between serum UII levels and high sensitivity C reactive peptide levels (r = 0.491, P < 0.001) and a significant negative correlation between serum UII levels and total proteins (r = -0.306, P = 0.032). Additionally, there was a significant positive correlation between serum UII levels with both systolic (r = 0.387, P = 0.005) and diastolic (r = 0.352, P = 0.012) blood pressure. Moreover, serum UII levels had a significant positive correlation with Ulcerative Colitis Endoscopic Index of Severity (r = 0.425, P = 0.048) and Simple Endoscopic Score for Crohn’s Disease (r = 0.466, P = 0.028) scores. Multiple linear regression analysis showed that serum UII levels retained significant association with high sensitivity C reactive peptide (β ± standard error, 0.262 ± 0.076, P < 0.001) and systolic blood pressure (0.040 ± 0.017, P = 0.030).CONCLUSIONIt is possible that UII is involved in the complex pathophysiology of cardiovascular complications in IBD patients, and its purpose should be investigated in further studies.     

Thymidine phosphorylase: A potential new target for treating cardiovascular disease

We recently found that thymidine phosphorylase (TYMP), also known as platelet-derived endothelial cell growth factor, plays an important role in platelet activation in vitro and thrombosis in vivo by participating in multiple signaling pathways. Platelets are a major source of TYMP. Since platelet-mediated clot formation is a key event in several fatal diseases, such as myocardial infarction, stroke and pulmonary embolism, understanding TYMP in depth may lead to uncovering novel mechanisms in the development of cardiovascular diseases. Targeting TYMP may become a novel therapeutic for cardiovascular disorders. In this review article, we summarize the discovery of TYMP and the potential molecular mechanisms of TYMP involved in the development of various diseases, especially cardiovascular diseases. We also offer insights regarding future studies exploring the role of TYMP in the development of cardiovascular disease as well as in therapy.     

Urotensin II level is elevated in inflammatory bowel disease patients

It was reported that the urotensin II (U-II) level in inflammatory bowel disease (IBD) patients are significantly higher than in controls. To provide future guidance for the management of cardiovascular risk factors in IBD patients, the sample size of the current study appears to be limited, and more clinical samples to compare U-II levels in IBD patients and controls are needed. This will clarify the possible roles of inflammation factors and related signaling pathways (like EPK1/2, NF-κB and Rho/ROCK) in the pathophysiology of IBD. Therefore, large multicenter studies should be done to confirm the findings and underlying mechanisms in the future.     

Autophagy as a therapeutic target in cardiovascular disease

The epidemic of heart failure continues apace, and development of novel therapies with clinical efficacy has lagged. Now, important insights into the molecular circuitry of cardiovascular autophagy have raised the prospect that this cellular pathway of protein quality control may be a target of clinical relevance. Whereas basal levels of autophagy are required for cell survival, excessive levels - or perhaps distinct forms of autophagic flux - contribute to disease pathogenesis. Our challenge will be to distinguish mechanisms that drive adaptive versus maladaptive autophagy and to manipulate those pathways for therapeutic gain. Recent evidence suggests this may be possible. Here, we review the fundamental biology of autophagy and its role in a variety of forms of cardiovascular disease. We discuss ways in which this evolutionarily conserved catabolic mechanism can be manipulated, discuss studies presently underway in heart disease, and provide our perspective on where this exciting field may lead in the future. This article is part of a special issue entitled ‘‘Key Signaling Molecules in Hypertrophy and Heart Failure.’’     

Identifying early cardiovascular disease to target candidates for treatment

Most attempts to identify individuals at risk for cardiovascular morbid events have involved screening for risk factors. These traditional risk factors do not identify the underlying atherosclerotic disease nor assess the severity of disease in individual patients. The goal for identifying a marker or markers for early cardiovascular disease that could serve as a surrogate for disease progression and ultimate morbid events is to improve the precision for early detection and treatment. The authors utilize a variety of techniques, which consist of 7 vascular tests (large and small artery elasticity, resting blood pressure and exercise blood pressure response, optic fundus photography, carotid intimal-media thickness, and microalbuminuria) and 3 cardiac tests (electrocardiography, [N-terminal pro-] B-type natriuretic peptide, and left ventricular ultrasonography). Each test is individually scored, and the total disease score is the sum of all the test scores. A study is ongoing to compare the new disease score vs the classical Framingham risk estimate in the prediction of cardiovascular events.     

Prasugrel: a new antiplatelet drug for the prevention and treatment of cardiovascular disease

Prasugrel, trade name Effient, is an investigational new antiplatelet drug currently under review for clinical use by the Food and Drug Administration. It is a thienopyridine analog with a structure similar to that of clopidogrel and ticlopidine. Thienopyridine derivatives inhibit platelet aggregation induced by adenosine diphosphate by irreversibly inhibiting the binding of adenosine diphosphate to the purinergic P2Y12 receptor on the platelet surface. Prasugrel has been shown to be a potent antiplatelet agent with a faster, more consistent, and greater inhibition of platelet aggregation compared with clopidogrel. It is debatable, however, how effectively these pharmacologic benefits will translate to clinical benefits. The results of the large TRITON-TIMI 38 trial, which compared prasugrel and clopidogrel in patients with acute coronary syndrome who were scheduled to receive coronary stents, demonstrated a significant reduction in ischemic events, including stent thrombosis, with prasugrel, but with an increased risk of major bleeding. The exact role of prasugrel in the management of ischemic heart disease is still being defined, but the risk:benefit ratio will likely play a major role in directing the best place for therapy with this new agent.     

The neuroimmune guidance cue netrin-1: A new therapeutic target in cardiovascular disease

Netrins are a family of proteins involved in cell migration and axon guidance during embryogenesis. The different functions and mechanisms of action of this family of proteins have been better characterized with the study of netrin-1. They are chemotropic and act as a bifunctional regulator of neuron migration. Apart from its role in the central nervous system, researchers have proven that netrin-1 plays a role in the development and formation of non-neural tissue; netrin-1 is thereby involved in regulation of cancers, cardiovascular diseases, kidney diseases, and other diseases. Concerning the cardiovascular realm, netrin-1 promotes angiogenesis and accelerates atherosclerosis, protects the heart against ischemia–reperfusion injury, and reduces the infarct size. These findings make the neuroimmune guidance cue netrin-1 an important therapeutic target. This work seeks to review the subject based on studies that have been conducted over the past decade to identify the perspectives and extent of the research on this protein in the field of cardiology.