Colon Ischemia: Recent Insights and Advances

Ischemic colitis is the most common manifestation of ischemic injury to the gastrointestinal tract, and the variety of defined causes is increasing. Local hypoperfusion and reperfusion injury are both thought to contribute to the disease process, which manifests with a wide spectrum of injury including reversible colopathy (subepithelial hemorrhage and edema), transient colitis, chronic colitis, stricture, gangrene, and fulminant universal colitis. The distribution is typically segmental. Older studies showed that any portion of the colon can be involved; recently, it was established that the site of involvement and prognosis can be correlated. In particular, isolated involvement of the right side of the colon was shown to have a different presentation and worse outcome than ischemic colitis involving other segments. Diagnosis is usually made clinically and supported by radiologic imaging and colonoscopic evaluation. Most patients respond to conservative supportive therapy, although some with severe disease require surgical intervention.     

Coronary Calcium: New Insights, Recent Data, and Clinical Role

Antiplatelet therapy with aspirin and a platelet P2Y12 receptor antagonist reduces thrombotic and ischemic events after percutaneous coronary intervention and acute coronary syndrome. The platelet inhibitory effect of the thienopyridine clopidogrel varies widely among individuals, and high on-treatment platelet reactivity has been associated with a substantial hazard for post-PCI cardiovascular events, including stent thrombosis. The clinical availability of ex vivo methods to measure the antiplatelet effect of P2Y12 antagonists raises the possibility that incorporating platelet function testing into clinical practice could facilitate a stratified and efficient approach to antiplatelet therapy following PCI, although data from definitive randomized trials supporting a routine approach are currently lacking.     

血管紧张素Ⅱ受体1阻滞剂心脏保护作用的研究近况

血管紧张素Ⅱ受体1阻滞剂(ARBs)有效阻断肾素-血管紧张素-醛固酮系统过度激活,抑制病理刺激导致的心脏结构重构、亚细胞重构和电重构.现从以上三方面对ARBs的心脏保护机制作一综述.     

Angiotensin II Receptors and Angiotensin II-Stimulated Signal Transduction

Originally known to be a vasoconstrictor and thought to play a critical role in hypertension, angiotensin II has recently emerged to be important in inflammation, atherosclerosis, and congestive heart failure. The discovery of selective angiotensin II receptor antagonists has enabled specific functions to be assigned to at least three angiotensin receptor subtypes (AT1, AT2, and AT4 receptors), which are expressed in a tissue-specific manner. Use of these antagonists resulted in the cloning and sequencing of two angiotensin II receptors (AT1 and AT2), which enabled a molecular analysis of angiotensin II binding sites to be performed. With these tools it has become possible to characterize the multiple signal transduction pathways activated by angiotensin II in a receptor- and tissue-specific manner. Initial studies have focused on the AT1 receptor inhibited by losartan and have defined structural domains responsible for G-protein coupling, activation of phospholipase C, and interactions with tyrosine kinases. Three major intracellular signal pathways associated with the AT1 receptor are activation of tyrosine kinases and downstream kinase cascades, stimulation of phospholipase C and increases in intracellular calcium, and inhibition of adenyl cyclase. Recent data show that angiotensin II not only stimulates cytoplasmic tyrosine kinases, including c-Src, focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2), but also may transactivate receptor tyrosine kinases such as EGF Axl and PDGF by as yet undefined autocrine mechanisms. These angiotensin II-stimulated signal cascades appear to be required for angiotensin II effects such as vasoconstriction, proto-oncogene expression, protein synthesis, and cell proliferation. Advances in our knowledge of angiotensin II-mediated signaling events, especially those related to stimulation of kinase activity, may aid in development of new therapies for cardiovascular diseases.     

Angiotensin II and adrenocorticotropin release: mediation by endogenous corticotropin-releasing factor

Recent reports indicate that the main effect of systemically administered angiotensin II (AII) on ACTH release is probably due to some central nervous system mechanism. The present studies were designed to investigate whether the central action of AII on ACTH release is directly mediated through CRF. In order to test the participation of endogenous CRF in the AII-induced ACTH release in vivo, intact and pharmacologically blocked (pretreated with chlorpromazine-morphine-nembutal) female rats were injected iv with AII (8 nmol/100 g BW). Plasma levels of ACTH as well as CRF content in the median eminence (ME) and medial basal hypothalamus (MBH) were evaluated before and 1, 2.5, and 5 min after treatment. These responses were compared with the effect of 1 min ether exposure on hypothalamic CRF content and plasma ACTH levels in unanesthetized animals. AII injection and ether exposure increased plasma ACTH levels several-fold at both 2.5 and 5 min post treatment in intact rats. Conversely, AII failed to induce any significant increase in plasma ACTH levels in centrally blocked rats at any interval studied. On the other hand, AII injection and ether inhalation acted in similar fashion on CRF content in ME, inducing fast depletion at 1 min post treatment, recovering to control values at 2.5 min after injection, and finally, accumulating peptide at 5 min post treatment. In addition, CRF content in the MBH decreased significantly at 5 min, under both experimental conditions; AII had no effect on hypothalamic CRF content in centrally blocked rats. In vitro experiments using whole MBH (containing ME) fragments incubated with either neural peptides or high K+ solutions indicate that AII possesses a CRF releasing effect at concentrations of 10(-6) M or more. Conversely, other hypothalamic peptides, such as LHRH, TRH, and somatostatin did not induce significant release of CRF at any of the concentrations assayed (10(-7) to 10(-5) M). On the other hand, high K+ solutions released CRF in a concentration-related manner (15-60 mM). These studies suggest that the central effect of AII stimulation on ACTH release in vivo could be, at least in part, through the release of hypothalamic CRF into the portal circulation.     

Induction of Angiotensinogen Synthesis and Secretion by Angiotensin II

ABSTRACT

The effect of angiotensin II (ANG II) on the secretion of angiotensinogen was studied in isolated rat hepatocytes, obtained by the collagenase perfusion technique and Percoll-density gradient centrifugation, and in the isolated perfused rat liver. In isolated hepatocytes, steady state concentrations of about 1, 10 or 100 nM of ANG II during 90 min of preincubation resulted in a 5, 27 and 33% increase of angiotensinogen secreted during a subsequent 3 hour incubation period. Secretion rates during the last hour of incubation were increased by about 70% by the two higher ANG II concentrations, as compared to controls. Hydrocortisone also induced an increased secretion of angiotensinogen in hepatocytes. The effect of ANG II was prevented by saralasin, a competitive ANG II antagonist and by actinomycin D. ANG II had no effect of the rate of albumin secretion and of total protein secretion. In the isolated perfused liver, ANG II induced a similar increase of angiotensinogen secretion, without affecting albumin and total protein secretion rates. These observations are consistent with the view that ANG II is participating in a feed back stimulation system of angiotensinogen synthesis and secretion in vivo.     

Functional Angiotensin Receptor on Cultured Bovine Chromaffin Cells: Secretory Response to Angiotensin II and Angiotensin III

ABSTRACT

The adrenal medulla responds in vivo to exogenous angiotensin II by secreting catecholamines. We previously reported that an angiotensin receptor is present on cultured bovine chromaffin cells and mediates secretion of adrenal catecholamines. The present report examines whether the bovine chromaffin cell receptor responds to angiotensin III. We show in this report that angiotensin III is nearly equiactive with angiotensin II as a secretagogue in these cultured cells.     

Biological Activation of Inert Ceramics: Recent Advances Using Tailored Self-Assembled Monolayers on Implant Ceramic Surfaces

High-strength ceramics as materials for medical implants have a long, research-intensive history. Yet, especially on applications where the ceramic components are in direct contact with the surrounding tissue, an unresolved issue is its inherent property of biological inertness. To combat this, several strategies have been investigated over the last couple of years. One promising approach investigates the technique of Self-Assembled Monolayers (SAM) and subsequent chemical functionalization to create a biologically active tissue-facing surface layer. Implementation of this would have a beneficial impact on several fields in modern implant medicine such as hip and knee arthroplasty, dental applications and related fields. This review aims to give a summarizing overview of the latest advances in this recently emerging field, along with thorough introductions of the underlying mechanism of SAMs and surface cell attachment mechanics on the cell side.     

Angiotensin II and Cardiac Fibrosis

The renin-angiotensin system has been linked to the pathogenesis of cardiac fibrosis through the use of experimental animal models and by clinical studies. This review emphasizes recent findings implicating the direct action of angiotensin II on cardiac cell types, particularly the cardiac fibroblast, as a causative factor in the development of cardiac fibrosis. The possible influence of other factors acting in concert with angiotensin II either to increase or to attenuate the fibrotic process is also discussed. Nitric oxide is considered as an example of a paracrine agent that can antagonize either the hemodynamic or cellular effects of angiotensin II during both physiological and pathological processes. (Trends Cardiovasc Med 1996;6:193-198).     

AngⅡ受体拮抗剂科素亚临床应用进展

血管紧张素(Ang)作用于血管平滑肌细胞使血管收缩、外周血管阻力增加;促使醛固醇产生和释放、增加水、钠潴留;刺激交感神经系统、促进去甲肾上腺素释放;Ang还刺激血管平滑肌细胞及心肌细胞的增殖、肥大,促进心脏纤维化。Ang的所有这些生物作用均通过细胞膜表面受体介导。A...     

Angiotensin II and oxidative stress

PURPOSE OF REVIEW: Angiotensin II regulates vasoconstriction, homeostasis of salt and water, and cardiovascular hypertrophy and remodeling. Angiotensin II is a potent activator of NAD(P)H oxidase in the cardiovascular system, and augments production of reactive oxygen species. Numerous signaling pathways in response to angiotensin II are mediated by reactive oxygen species and oxidative stress is deeply associated with the progression of cardiovascular disease. The purpose of this review is to discuss the mechanism of reactive oxygen species formation and the pathophysiological effects of angiotensin II in the cardiovascular system. RECENT FINDINGS: Recent studies have demonstrated novel molecular mechanisms of reactive oxygen species generation by angiotensin II and signaling pathways including cell proliferation, hypertrophy and apoptosis. In spite of these findings that strongly suggest the benefits of angiotensin II inhibition for cardiovascular disease, the clinical effects of angiotensin II-induced reactive oxygen species on the cardiovascular system are still controversial. SUMMARY: We focus on the effects of angiotensin II-induced oxidative stress on cardiovascular function and remodeling after discussing the source of reactive oxygen species and novel signaling pathways in response to reactive oxygen species.     

Angiotensin II and Vascular Injury

Vascular injury, characterized by endothelial dysfunction, structural remodelling, inflammation and fibrosis, plays an important role in cardiovascular diseases. Cellular processes underlying this include altered vascular smooth muscle cell (VSMC) growth/apoptosis, fibrosis, increased contractility and vascular calcification. Associated with these events is VSMC differentiation and phenotypic switching from a contractile to a proliferative/secretory phenotype. Inflammation, associated with macrophage infiltration and increased expression of redox-sensitive pro-inflammatory genes, also contributes to vascular remodelling. Among the many factors involved in vascular injury is Ang II. Ang II, previously thought to be the sole biologically active downstream peptide of the renin-angiotensin system (RAS), is converted to smaller peptides, [Ang III, Ang IV, Ang-(1-7)], that are functional and that modulate vascular tone and structure. The actions of Ang II are mediated via signalling pathways activated upon binding to AT₁R and AT₂R. AT₁R activation induces effects through PLC-IP₃-DAG, MAP kinases, tyrosine kinases, tyrosine phosphatases and RhoA/Rho kinase. Ang II elicits many of its (patho)physiological actions by stimulating reactive oxygen species (ROS) generation through activation of vascular NAD(P)H oxidase (Nox). ROS in turn influence redox-sensitive signalling molecules. Here we discuss the role of Ang II in vascular injury, focusing on molecular mechanisms and cellular processes. Implications in vascular remodelling, inflammation, calcification and atherosclerosis are highlighted.     

Tissue-Specific Regulation of Growth Factors and Clusterin by Angiotensin II

Angiotensin II (ANG II) has been implicated in the hypertrophic and fibrotic responses of the heart and kidney to systemic hypertension. To determine whether these actions of ANG II are related to tissue-specific stimulation of growth factors, we infused adult Sprague-Dawley rats with ANG II at 50 ng/min (low dose), 100 ng/min (high dose), or vehicle for 1 week. Rats receiving vehicle or low-dose ANG II were normotensive with normal plasma aldosterone concentration, whereas rats receiving high-dose ANG II were hypertensive with increased plasma aldosterone. Tissue fibrosis was quantified morphometrically, and messenger RNA (mRNA) for transforming growth factor-β₁ (TGF-β₁) and prepro-epidermal growth factor (EGF) was measured in liver, heart, and renal glomeruli and tubules. In addition, mRNA was determined for clusterin, a glycoprotein expressed in response to tissue injury. Compared to vehicle, low-dose ANG II increased TGF-β₁ expression in glomeruli, tubules, and heart, but not in liver, and increased EGF expression in renal tubules only. High-dose ANG II decreased clusterin expression in liver only. Fibrosis was induced by low- and high-dose ANG II in kidney and heart, but not in liver. We conclude that ANG II selectively stimulates TGF-β₁ mRNA in the heart and kidney, which may contribute to cardiac and renal interstitial fibrosis resulting from activation of the renin-angiotensin system independent of hypertension. By stimulating cellular proliferation, selective stimulation by ANG II of EGF in renal tubules may amplify the effects of TGF-β₁. Suppression of clusterin expression in the liver of hypertensive rats may represent a specific response to high levels of circulating ANG II or a response to hypertensive injury.     

Sublingual Immunotherapy: Recent Advances

The practice of administering sublingual immunotherapy for respiratory allergy is gaining more and more diffusion worldwide as a consequence of the robust demonstration of clinical efficacy and safety provided by recent high-powered and well-designed studies, confirming for individual seasonal allergens the results of previous metanalyses in adult and pediatric populations. Preliminary evidence derives from recent rigorous trials on perennial allergens, like house dust mites, and specifically designed studies addressed the benefits on asthma. Emerging research suggests that SLIT may have a future role in other allergic conditions such as atopic dermatitis, food, latex and venom allergy. Efforts to develop a safer and more effective SLIT for inhalant allergens have led to the development of allergoids, recombinant allergens and formulations with adjuvants and substances targeting antigens to dendritic cells that possess a crucial role in initiating immune responses. The high degree of variation in the evaluation of clinical effects and immunological changes requires further studies to identify the candidate patients to SLIT and biomarkers of short and long term efficacy. Appropriate management strategies are urgently needed to overcome the barriers to SLIT compliance.