利钠肽家族基因与心血管疾病研究新进展

利钠肽家族是一组由心肌细胞分泌的激素,主要包括A型、B型和C型利钠肽,具有相似的基因结构和生理学效应,可对心血管系统产生血压调节、抗心肌肥厚、抗心肌纤维化和抗心肌弛缓等保护作用。利钠肽受体A、B和C亦介导多种生理活性,调节心血管稳态。利钠肽受体A选择性结合A型、B型利钠肽。利钠肽受体B结合C型利钠肽。利钠肽受体C结合各型利钠肽,通过受体介导的内化和退化作用清除血液循环中利钠肽。对利钠肽家族及其受体基因单核甘酸多态性及功能研究显示,其与多种心血管疾病(房颤、高血压、心力衰竭等)的易感性相关。利钠肽家族及其受体基因缺失的转基因小鼠表现为心肌肥厚、心肌纤维化,与高血压、心肌病及心力衰竭的发生发展相关。各种导致心肌肥厚和缺血性损伤的刺激均参与利钠肽及其受体基因的表达调控。临床将脑钠肽作为左室功能障碍和心力衰竭失代偿的一个预测指标。静脉注射重组脑钠肽已经成为治疗急性心力衰竭的有效手段。深入了解利钠肽家族基因变异及其信号调控有助于探索心血管疾病的病理生理机制,为临床诊疗开辟新思路。     

利钠肽家族基因与心血管疾病研究新进展

利钠肽家族是一组由心肌细胞分泌的激素, 主要包括A型、B型和C型利钠肽, 具有相似的基因结构和生理学效应, 可对心血管系统产生血压调节、抗心肌肥厚、抗心肌纤维化和抗心肌弛缓等保护作用。利钠肽受体A、B和C亦介导多种生理活性, 调节心血管稳态。利钠肽受体A选择性结合A型、B型利钠肽。利钠肽受体B结合C型利钠肽。利钠肽受体C结合各型利钠肽, 通过受体介导的内化和退化作用清除血液循环中利钠肽。对利钠肽家族及其受体基因单核甘酸多态性及功能研究显示, 其与多种心血管疾病(房颤、高血压、心力衰竭等)的易感性相关。利钠肽家族及其受体基因缺失的转基因小鼠表现为心肌肥厚、心肌纤维化, 与高血压、心肌病及心力衰竭的发生发展相关。各种导致心肌肥厚和缺血性损伤的刺激均参与利钠肽及其受体基因的表达调控。临床将脑钠肽作为左室功能障碍和心力衰竭失代偿的一个预测指标。静脉注射重组脑钠肽已经成为治疗急性心力衰竭的有效手段。深入了解利钠肽家族基因变异及其信号调控有助于探索心血管疾病的病理生理机制, 为临床诊疗开辟新思路。     

Natriuretic peptides in cardiovascular diseases

The natriuretic peptide family comprises atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), dendroaspis natriuretic peptide (DNP), and urodilatin. The activities of natriuretic peptides and endothelins are strictly associated with each other. ANP and BNP inhibit endothelin-1 (ET-1) production. ET-1 stimulates natriuretic peptide synthesis. All natriuretic peptides are synthesized from polypeptide precursors. Changes in natriuretic peptides and endothelin release were observed in many cardiovascular diseases: e.g. chronic heart failure, left ventricular dysfunction and coronary artery disease.     

Natriuretic peptides: their role in diagnosis and therapy

Cardiac natriuretic peptide hormones, atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP), are synthesized and secreted by the heart, producing several biological effects, such as natriuresis, vasorelaxation and hypotension. During the last decade these peptides, especially BNP, have received increasing attention as potential markers of cardiovascular disease. Their measurements can be used to diagnose heart failure, including diastolic dysfunction, and using them has been shown to save money. BNP levels can enable the differentiation between dyspnoic patients secondary to ventricular dysfunction and subjects with primary respiratory disorders. Moreover, there is good evidence that natriuretic peptides may have a diagnostic role in arterial hypertension, acute coronary syndromes, pulmonary hypertension, some valvular heart disease and some disorders affecting other systems (diabetes or thyroid disorders). In this paper we discuss the clinical utility of assessment of natriuretic peptide hormones in the diagnosis of various clinical conditions and their use as pharmacological agents.     

利钠肽系统与肾素-血管紧张素-醛固酮系统在心力衰竭中交互作用

慢性心力衰竭是以高发病率、高入院率及高死亡率为特征的临床综合征,也是各种心血管疾病发展的终末阶段。神经激素系统的激活在心力衰竭病理生理中起着关键作用,其以肾素-血管紧张素-醛固酮系统(RAAS)、交感神经系统(SNS)及利钠肽系统(NPs)为主要组成部分。在心衰的病理生理中,NPs与RAAS存在交互作用,其对于与心功能不全相关的血液动力学改变与组织重塑起重要的作用,并且最终可导致心衰的恶化。因此,能够同时作用于RAAS与NPs,并且能够纠正两者间调节紊乱的干预措施,对于慢性心衰的治疗将具有良好的疗效。本文将主要对RAAS、NPs及NPs与RAAS的交互作用在心衰中的病理生理作用进行综述,并展望针对NPs与RAAS的交互作用的临床应用前景。     

Relevance of the assessment of natriuretic peptide plasma concentrations in hypertensive pregnant women

Abstract

Assessment of the plasma concentrations of natriuretic peptides (NPs) is widely used to diagnose and evaluate the progression of cardiac failure, and their potential as markers of preeclampsia (PE) has been examined in recent years. It has been established that plasma concentrations of NPs do not change in the course of normal pregnancy. However, elevated levels of these peptides may have a prognostic value in patients with PE. This study presents information about the relevance of NPs assessment in the evaluation of physiological pregnancy, as well as in pregnancy complicated with arterial hypertension. The most commonly examined NPs is the N-terminal fragment of the brain natriuretic peptide (NT-proBNP), and it may be prognostic marker of PE and other complications of pregnancy.     

Immunoreactive forms of natriuretic peptides in ovine brain: response to heart failure

In order to elucidate how brain natriuretic peptides (NPs) are affected by experimentally induced heart failure, we have measured the immunoreactive (IR) levels of the NP in extracts from 10 regions of ovine brain, including pituitary, and clarified their molecular forms using high performance liquid chromatography (HPLC). Using species-specific radioimmunoassay (RIA), atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were all detected in extracts taken from control animals and sheep that had undergone rapid ventricular pacing for 7 days to induce heart failure. CNP was the most abundant NP as assessed by specific RIA, and the pituitary contained the highest IR levels for all three NP. Compared with control animals, the pituitary content of BNP in animals with heart failure was reduced by 40% (control, 0.26±0.02 pmol/g wet weight versus heart failure 0.16±0.01; P<0.01, n=7). No other significant changes were observed. The molecular forms of ANP and CNP in whole brain extracts as assessed by HPLC were proANP and CNP22, CNP53 and proCNP, respectively. BNP in pituitary extracts was assessed to be primarily proBNP with a minor component of mature BNP26.     

Recent advances in natriuretic peptide research

The natriuretic peptides are a family of related hormones that play a crucial role in cardiovascular and renal homeostasis. They have recently emerged as potentially important clinical biomarkers in heart failure. Natriuretic peptides, particularly brain natriuretic peptide (BNP) and the inactive N-terminal fragment of BNP, NT-proBNP, that has an even greater half-life than BNP, are elevated in heart failure and therefore considered to be excellent predictors of disease outcome. Nesiritide, a recombinant human BNP, has been shown to provide symptomatic and haemodynamic improvement in acute decompensated heart failure, although recent reports have suggested an increased short-term risk of death with nesiritide use. This review article describes: the current use of BNP and its inactive precursor NT-proBNP in diagnosis, screening, prognosis and monitoring of therapy for congestive heart failure, the renoprotective actions of natriuretic peptides after renal failure and the controversy around the therapeutic use of the recombinant human BNP nesiritide.     

Tailored therapy for heart failure: neurohormones

Plasma B type cardiac natriuretic peptides reflect cardiac structure and function and have proven roles in assisting in the diagnosis of acute heart failure. They are also powerful independent prognostic indicators across the full spectrum of cardiovascular disease. The efficacy of serial measurements of plasma B type peptides in guiding titration of therapy for chronic heart failure has been the subject of a number of randomized controlled trials. These are summarized in the following brief review. In the decade 2000-2010, 8 trials have been completed. Study design, the characteristics of the heart failure population studied, duration of follow-up, the exact end points recorded, and target peptide levels pursued all differ somewhat between trials. However, an overall consistency is emerging, supported by 2 metaanalyses. In aggregate, the existing trial data suggest that adjustment of treatment in chronic heart failure according to serial B type peptide measurements used in conjunction with established clinical methods is likely to reduce cardiac mortality and admissions with heart failure, at least in those patients aged under 75?years with impaired left ventricular systolic function.     

Adrenomedullin and heart failure

Evidence suggests that adrenomedullin (AM) plays a role in the pathophysiology of heart failure. Circulating concentrations of AM are elevated in cardiovascular disease in proportion to the severity of cardiac and hemodynamic impairment. Raised plasma AM levels following acute cardiac injury and in heart failure provide prognostic information on adverse outcomes. In heart failure, elevated circulating AM also identifies patients likely to receive long-term benefit from inclusion of additional anti-failure therapy (carvedilol). Administration of AM in experimental and human heart failure induces reductions in arterial pressure and cardiac filling pressures, and improves cardiac output, in association with inhibition of plasma aldosterone (despite increased renin release) and sustained (or augmented) renal glomerular filtration and sodium excretion. Furthermore, AM in combination with other therapies (angiotensin-converting enzyme inhibition and augmentation of the natriuretic peptides) results in hemodynamic and renal benefits greater than those achieved by the agents separately. Manipulation of the AM system holds promise as a therapeutic strategy in cardiac disease.     

Pathophysiologic relevance of measuring the plasma levels of cardiac natriuretic peptide hormones in humans.

Cardiac natriuretic peptides (ANP, BNP, and biologically active peptides of the N-terminal proANP1-98) are differently regulated in their production/secretion patterns and clearance rates; consequently, the assay for these peptides may provide complementary (or even different) pathophysiological and/or clinical information. The assay for cardiac natriuretic peptides has been utilized in clinical conditions associated with expanded fluid volume. In particular, this assay can be useful in discriminating between normal subjects and patients in different stages of heart failure and can also be considered a prognostic indicator of long-term survival in patients with heart failure and/or after acute myocardial infarction. Non-competitive immunometric assays (such as two-site IRMAs), even if more expensive, seem to be preferable to RIAs for routinary assay of cardiac peptide hormones because they generally have a better degree of sensitivity, accuracy, and precision.     

Regulation of expression of atrial and brain natriuretic peptide,biomarkers for heart development and disease

The mammalian heart expresses two closely related natriuretic peptide (NP) hormones, atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP). The excretion of the NPs and the expression of their genes strongly respond to a variety of cardiovascular disorders. NPs act to increase natriuresis and decrease vascular resistance, thereby decreasing blood volume, systemic blood pressure and afterload. Plasma levels of BNP are used as diagnostic and prognostic markers for hypertrophy and heart failure (HF), and both ANF and BNP are widely used in biomedical research to assess the hypertrophic response in cell culture or the development of HF related diseases in animal models. Moreover, ANF and BNP are used as specific markers for the differentiating working myocardium in the developing heart, and the ANF promoter serves as platform to investigate gene regulatory networks during heart development and disease. However, despite decades of research, the mechanisms regulating the NP genes during development and disease are not well understood. Here we review current knowledge on the regulation of expression of the genes for ANF and BNP and their role as biomarkers, and give future directions to identify the in vivo regulatory mechanisms. This article is part of a Special Issue entitled: Heart failure pathogenesis and emerging diagnostic and therapeutic interventions.     

The endocrine heart and natriuretic peptides: histochemistry, cell biology, and functional aspects of the renal urodilatin system

 This review focuses on some selected aspects of the endocrine heart and natriuretic peptides. The endocrine heart is composed of specific myoendocrine cells of the cardiac atria. The myoendocrine cells synthesize and secrete the natriuretic peptide hormones which exhibit natriuretic, diuretic, and vasorelaxant properties. Immunohistochemical analyses show that natriuretic peptides of the A-type and B-type are localized not only in the specific granules of these myoendocrine cells but also in many other organs including the brain, adrenal medulla, and kidney. Also, their receptors are detected in many organs showing the multiple functions of these regulatory peptides. Of the members of the natriuretic peptide family, ANP (ANP for atrial natriuretic peptide; also denominated cardiodilatin, CDD), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), and the A-type, including its renal form, urodilatin, are emphasized in this review. Urodilatin is localized in the kidney, differentially processed, and secreted into the urine. The intrarenal synthesis and secretion is the basis for a paracrine system regulating water and sodium reabsorption at the level of the collecting duct. CDD/ANP-1-126, cleaved from a precursor of 126 amino acids in the heart to a 28-amino acid-containing circulating molecular form (CDD/ANP-99-126), and urodilatin (CDD/ANP-95-126) share similar biochemical features and biological functions, but urodilatin may be more involved in the regulation of body fluid volume and water–electrolyte excretion, while circulating CDD/ANP-99-126 is responsible for blood pressure regulation. The physiological and pharmacological properties of these peptides have great clinical impact, and as a consequence urodilatin is involved in drug development for the treatment of acute renal failure, cardiomyopathia, and acute asthma. Accepted: 8 July 1998     

利钠肽在急性心力衰竭预后评估及指导治疗中的作用

利钠肽(BNP与NT-proBNP)是预测急性心衰预后及评估急性心衰治疗效果可靠的指标.日常临床决策加用利钠肽检测提高了急性心衰高危患者的发现率,而这些患者往往需要加强追踪及强化治疗.现就利钠肽在评估急性心衰预后及指导心衰治疗中的价值作如下综述.     

Atrial natriuretic peptides in heart failure: pathophysiological significance, diagnostic and prognostic value

Neurohormonal activation in patients with heart failure is dominated by the deleterious long-term effects of activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. The natriuretic peptides, including brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP), are also upregulated in heart failure, and partially counteract these deleterious effects by promoting vasodilation, natriuresis, and diuresis. Although BNP has been established as an important biomarker in the diagnosis and prognosis of heart failure, growing evidence suggests that measurement of plasma ANP, specifically its metabolite mid-regional pro-ANP, has similar diagnostic and prognostic value. Furthermore, its measurement may provide incremental diagnostic value when BNP levels fall into "grey zone" levels and may be a more potent prognostic marker of mortality.     

Cardiovascular and renal effects of eel and rat atrial natriuretic peptide in rainbow trout,Salmo gairdneri

Summary The renal and in vitro vascular effects of atrial natriuretic peptides have been examined in seveal species of fish. However, comparatively few investigations have described the effects of these peptides on the cardiovascular system in vivo. In the present experiments the dorsal aorta and urinary bladder were cannulated and the effects of atrial natriuretic peptides from rat and eel were monitored in conscious trout during bolus injection or continuous atrial natriuretic peptide infusion. The results show that the initial pressor effect of atrial natriuretic peptides is independent of environmental salinity adaptation (fresh or seawater) and the chemical form of atrial natriuretic peptide injected, but it is affected by the rate of atrial natriuretic peptide administration. This pressor response, and the accompanying diuresis, are mediated through -adrenergic activation. Continuous infusion of either rat or eel atrial natriuretic peptide produces a steady fall in mean arterial blood pressure, which is temporally preceded by an increase in heart rate and a decrease in pulse pressure. Diuresis induced by atrial natriuretic peptides is only partially sustained during continuous infusion. Propranolol partially blocks the increase induced in heart rate by atrial natriuretic peptides, but does not affect either pulse pressure or mean arterial pressure. Propranolol significantly increases urine flow in saline-infused animals but has no apparent effect on animals subjected to infusions of atrial natriuretic peptides. These results indicate that there are multiple foci for the action of atrial natriuretic peptides in trout and that in many instances the effects of atrial natriuretic peptides are mediated through secondary effector systems.Abbreviations ANP atrial natriuretic peptide - bw body weight - PBS phosphate-buffered saline     

BN P 的测定和临床应用的研究进展

B型利钠肽是一种具有利尿作用的内源性肽,其对早期发现心衰病人、心衰病人的分级、区分心衰及其他原因引起的呼吸困难、监测心衰治疗、提示心衰病人预后、识别有无左室功能不全及急性冠脉综合症的风险评估方面具有重要临床应用价值。本文主要介绍了B型利钠肽的测定及临床应用。     

Guanylyl cyclase / atrial natriuretic peptide receptor-A: role in the pathophysiology of cardiovascular regulation

Atrial natriuretic factor (ANF), also known as atrial natriuretic peptide (ANP), is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and anti-proliferative effects, which are important in the control of blood pressure and cardiovascular events. One principal locus involved in the regulatory action of ANP and brain natriuretic peptide (BNP) is guanylyl cyclase / natriuretic peptide receptor-A (GC-A/NPRA). Studies on ANP, BNP, and their receptor, GC-A/NPRA, have greatly increased our knowledge of the control of hypertension and cardiovascular disorders. Cellular, biochemical, and molecular studies have helped to delineate the receptor function and signaling mechanisms of NPRA. Gene-targeted and transgenic mouse models have advanced our understanding of the importance of ANP, BNP, and GC-A/NPRA in disease states at the molecular level. Importantly, ANP and BNP are used as critical markers of cardiac events; however, their therapeutic potentials for the diagnosis and treatment of hypertension, heart failure, and stroke have just begun to be realized. We are now just at the initial stage of molecular therapeutics and pharmacogenomic advancement of the natriuretic peptides. More investigations should be undertaken and ongoing ones be extended in this important field.     

Cardiac endocrine function is an essential component of the homeostatic regulation network: physiological and clinical implications

The discovery of cardiac natriuretic hormones required a profound revision of the concept of heart function. The heart should no longer be considered only as a pump but rather as a multifunctional and interactive organ that is part of a complex network and active component of the integrated systems of the body. In this review, we first consider the cross-talk between endocrine and contractile function of the heart. Then, based on the existing literature, we propose the hypothesis that cardiac endocrine function is an essential component of the integrated systems of the body and thus plays a pivotal role in fluid, electrolyte, and hemodynamic homeostasis. We highlight those studies indicating how alterations in cardiac endocrine function can better explain the pathophysiology of cardiovascular diseases and, in particular of heart failure, in which several target organs develop a resistance to the biological action of cardiac natriuretic peptides. Finally, we emphasize the concept that a complete knowledge of the cardiac endocrine function and of its relation with other neurohormonal regulatory systems of the body is crucial to correctly interpret changes in circulating natriuretic hormones, especially the brain natriuretic peptide.