Ceramide: physiological and pathophysiological aspects

Ceramide generated in the cell membrane has been shown to be central for the induction of apoptosis by death receptors and many stress stimuli such as gamma-irradiation, UV-light or infection with pathogens. Ceramide reorganizes cell membranes and forms large ceramide-enriched membrane domains that serve the spatial and temporal organization of the cellular signalosome upon activation. Thus, ceramide-enriched membrane domains mediate clustering of CD95 and DR5 to facilitate apoptosis, and they are also critically involved in apoptosis after irradiation, UV-light and infection with Pseudomonas aeruginosa. Since ceramide-enriched membrane domains amplify signals, their function is not restricted to the induction of apoptosis and it was shown that ceramide-enriched membrane domains are also involved in internalization of pathogens and the control of cytokine release from infected epithelial cells. Recent studies support the notion that changes of the ceramide metabolism are also critically involved in human diseases, for instance neurological disorders, cancer, infectious diseases and Wilson's disease.     

钙网蛋白的生理及病理生理学作用

钙网蛋白（calreticulin,CRT）是内质网／肌浆网主要的Ca2^＋结合蛋白,通过协助蛋白质正确折叠和维持细胞Ca^2＋稳态而参与调节细胞凋亡、黏附、类固醇敏感性基因表达和自身免疫反应等,并与多种人类疾病的发生、发展和预后相关。本文综述钙网蛋白的生理功能及其在心肌肥大与衰竭、血管新生和应激等病理状态下的变化。     

骨骼的内分泌功能

既往认为骨骼是支持机体基本结构和参与运动及钙磷代谢的主要器官。近年发现组成骨骼的成骨细胞和破骨细胞能合成和分泌多种骨调节蛋白、生长因子、脂肪因子、炎症因子和心血管活性肽等多种生物活性物质,以旁/自分泌方式调节骨骼系统功能,并能通过血液循环远距分泌的方式,调节机体能量代谢、炎症反应和内分泌稳态等。     

Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart

Cardiotrophin-1 (CT-1), a member of the interleukin-6 superfamily of cytokines, possesses hypertrophic actions and atrial natriuretic peptide (ANP)-producing activity in vitro. The goal of our study is to elucidate whether CT-1 affects the cardiovascular system in vivo. Intravenous injection of CT-1 (4-100 microg/kg) in conscious rats evoked significant declines in blood pressure and reflex increases in heart rate (HR) in a dose-dependent manner. CT-1 induced no significant change in cardiac output (from 260.7 +/- 11.0 to 264.7 +/- 26.6 ml. min(-1). kg(-1), P = not significant), which was compatible with the results from isolated perfused rat hearts; HR, change in pressure over time, left ventricular developed pressure, and perfusion pressure were unaffected. Northern blot and RT-PCR analyses revealed that CT-1 increased expression of inducible nitric oxide synthase (iNOS) in lung and aorta but not in heart or liver. Pretreatment with aminoguanidine, a specific iNOS inhibitor, inhibited both iNOS mRNA production and the depressor effect of CT-1. Interestingly, CT-1 increased ventricular expression of ANP and brain natriuretic peptide (BNP). The data demonstrate that CT-1 elicits its hypotensive effect via a nitric oxide-dependent mechanism and that CT-1 induces ANP and BNP mRNA expression in vivo.     

Recent physiological and pathophysiological aspects of Parkinsonian movement disorders

Deficits in the neural control of limb movements constitute a major part of Parkinsonian symptoms and are linked to a decay of dopaminergic neurotransmission. In animal models, Parkinsonian-like hypokinesia is consistently reproduced with large nigrostriatal dopamine depletions, while tremor and rigidity are less readily obtained. Lesions leading to a less than 70% striatal dopamine depletion are largely compensated by an increased activity of dopamine terminals. With more important lesions, supersensitivity of striatal non-adenylate cyclase-linked dopamine receptors occurs. Electrophysiological studies in Parkinsonian patients demonstrate increased reaction times and a reduced build-up of movement-related muscular activity underlying hypokinesia and provide circumstantial evidence for a central origin of tremor and rigidity. Single cell activity in unlesioned, behaving monkeys shows an increasingly direct relationship to movements when following the neural connections from mid-brain dopamine cells via striatum, globus pallidus, thalamus to pyramidal tract neurons of motor cortex. These data corroborate experimentally the concept that Parkinsonian hypokinesia is due to a failure of basic behavioral activating mechanisms.     

Prostaglandin modulation of venoconstriction to physiological stress in normals and heart failure patients

Prostaglandins released from blood vessels modulate vascular tone, and inhibition of their production during exogenous infusions of catecholamines causes increased venoconstriction. To determine the influence of prostaglandin production on venoconstriction during physiological stimuli known to cause sympathetic activation, and to assess its importance in chronic heart failure (CHF), we studied 11 normal subjects (62 +/- 4 yr) and 14 patients with CHF (64 +/- 2 yr, left ventricular ejection fraction 23 +/- 1%, New York Heart Association classes II and III) (means +/- SE). Dorsal hand vein distension was measured during mental arithmetic (MA), cold pressor test (CPT), and lower body negative pressure (LBNP; -10 and -40 mmHg), with saline infusion in one hand and local indomethacin (cyclooxygenase inhibitor) infusion (3 microg/min) in the other. Acetylcholine (0.01-1 nmol/min) dilated veins preconstricted with PGF(2alpha) in normals but, consistent with endothelial dysfunction, barely did so in CHF patients (P = 0.001). Nonendothelial venodilation to sodium nitroprusside (0.3-10 nmol/min) was not different between normals and CHF patients. Resting venous norepinephrine levels were higher in CHF patients (2,812 +/- 420 pmol/l) than normals (1,418 +/- 145 pmol/l, P = 0.007). In normals, indomethacin caused increased venoconstriction to MA (from 4.9 +/- 1.5 to 19.2 +/- 4.5%, P = 0.022) and CPT (from 2.9 +/- 3.8 to 17.6 +/- 4.2%, P = 0.007). In CHF, indomethacin caused increased venoconstriction to MA (from 6.6 +/- 3.9% to 19.0 +/- 4.5%, P = 0.014), CPT (from 9.6 +/- 2.1% to 20.1 +/- 3.7%, P = 0.001), and -40 mmHg LBNP (from 10.7 +/- 3.0% to 23.2 +/- 3.8%, P = 0.041). Control responses for all tests were not different between normals and CHF patients. The effects of indomethacin on venoconstriction to MA and CPT were not different between normals and CHF patients, but venoconstriction to -40 mmHg LBNP was accentuated in CHF patients (P = 0.036). Inhibition of prostaglandins by indomethacin significantly enhances hand vein constriction to physiological stimuli in both normals and CHF patients, although a differential effect exists for LBNP.     

The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS

Adiponectin is an abundantly expressed adipokine in adipose tissue and has direct insulin sensitizing activity. A decrease in the circulating levels of adiponectin by interactions between genetic factors and environmental factors causing obesity has been shown to contribute to the development of insulin resistance, type 2 diabetes, metabolic syndrome and atherosclerosis. In addition to its insulin sensitizing actions, adiponectin has central actions in the regulation of energy homeostasis. Adiponectin enhances AMP-activated protein kinase activity in the arcuate hypothalamus via its receptor AdipoR1 to stimulate food intake and decreases energy expenditure. We propose a hypothesis on the physiological role of adiponectin: a starvation gene in the course of evolution by promoting fat storage on facing the loss of adiposity.     

Atrial BNP endocrine function during chronic unloading of the normal canine heart

The goal of the study was to define the effect of chronic unloading of the normal heart on atrial endocrine function with a focus on brain natriuretic peptide (BNP), specifically addressing the role of load and neurohumoral stimulation. Although produced primarily by atrial myocardium in the normal heart, controversy persists with regard to load-dependent vs. neurohumoral mechanisms controlling atrial BNP synthesis and storage. We used a unique canine model of chronic unloading of the heart produced by thoracic inferior vena caval constriction (TIVCC), which also resulted in activation of plasma endothelin (ET-1), ANG II, and norepinephrine (NE), known activators of BNP synthesis, compared with sham. TIVCC was produced by banding of the inferior vena cava for 10 days (n = 6), whereas in control (n = 5) the band was not constricted (sham). In a third group (n = 7), the band was released on day 11, thus acutely reloading the heart. Chronic TIVCC decreased cardiac output and right atrial pressure with a decrease in atrial mass index consistent with atrial atrophy. Atrial BNP mRNA decreased compared with sham. Immunoelectron microscopy revealed an increase in BNP in atrial granules consistent with increased storage. Acute reloading increased cardiac filling pressures and resulted in an increase in plasma BNP. We conclude that chronic unloading of the normal heart results in atrial atrophic remodeling and in suppression of atrial BNP mRNA despite intense stimulation by ET, ANG II, and NE, underscoring the primacy of load in the control of atrial endocrine function and structure.     

Overview of physiological and pathophysiological effects of thromboxane A2

Thromboxane (Tx) A2 is a biologically potent and chemically unstable metabolite of prostaglandin endoperoxides. Recent developments in measurement techniques and the availability of both selective inhibitors of Tx synthetase and TxA2 receptor antagonists have facilitated the implication of TxA2 as a physiological modulator and as a mediator in thrombotic, vasospastic, and bronchospastic conditions. TxA2 is synthesized by platelets and contributes to platelet activation and irreversible platelet aggregation in physiological hemostasis and in thrombosis (e.g., unstable angina, stroke). TxA2 is also synthesized in intestinal, pulmonary, and renal tissues by cells other than platelets. Particularly in these tissues, TxA2 appears to act as a physiological modulator of changes in blood flow distribution and airway caliber. Strong stimuli for TxA2 release from these tissues may initiate ulcer, pulmonary hypertension, bronchoconstriction, and renal vasoconstriction. Evidence supports participation of TxA2 and/or TxA2 receptors in modulation of natural cytotoxic cell cytotoxicity, in tumor growth and metastasis, in complications of pregnancy (e.g., preeclampsia), and in the progression of ischemic injury after coronary artery occlusion. This evidence supports pivotal involvement of TxA2 in pathophysiology and provides a strong rationale for pursuing TxA2-blocking strategies in drug development.     

Biomarkers for atherosclerosis: pathophysiological role and pharmacological modulation

PURPOSE OF REVIEW: The aim of this article is to discuss the potential value of biomarkers for atherosclerosis in the assessment of risk for cardiovascular disease, in the pathogenesis of atherosclerosis, and in the monitoring of pharmacological treatment. RECENT FINDINGS: In an attempt to improve global cardiovascular risk prediction, considerable effort has been made in the discovery and characterization of soluble biomarkers which can go beyond the measure of total and LDL cholesterol levels. In particular, circulating molecules related to chronic inflammation have emerged as potential biomarkers for atherosclerosis. Evidence, obtained from in-vitro and in-vivo experimental models, has also documented that the majority of biomarkers play a pathological role in atherogenesis. Multiple screening of different biomarkers may therefore improve the assessment of risk, diagnosis, and prognosis for cardiovascular disease. In addition, soluble biomarkers have been shown to be modulated by hypolipidemic drugs and to be potentially useful in determining the clinical benefits of pharmacological therapies that do not alter serum lipid levels. SUMMARY: Altered levels of soluble biomarkers are associated with cardiovascular disease, and profiling of multiple biomarkers for atherosclerosis will be a useful indicator for better risk assessment, diagnosis, and prognosis, as well as monitoring pharmacological treatments for atherosclerosis.     

Biochemical, physiological and pathophysiological aspects of intestinal diamine oxidase

Studies were performed on the distribution and properties of intestinal diamine oxidase (DAO) previously called histaminase. DAO activity is high in the gastrointestinal tract of all investigated species. The highest values are in the aboral part of the small intestine: where DAO is localized in the mucosa, predominantly in the top villus region. A high reaction velocity of human intestinal DAO is observed with putrescine, methylhistamine and histamine. H2 receptor antagonists and an agonist (impromidine) inhibit intestinal DAO. The physiological and pathophysiological significance of intestinal DAO in the regulation of histamine and putrescine levels is described, as is the possibility that DAO may act as a growth retardant.     

The heart as an endocrine organ

Modern data on atrial natriuretic factor (ANF) are presented. Synthesis of this factor, its storage and release from cardiac atria are described. The role of ANF in the body fluid volume regulation and blood pressure homeostasis is discussed. ANF is regarded as a circulating hormone.     

The heart as an endocrine organ

The discovery of atrial natruietic peptide firmly established that the heart was not just a pump and provided the long-sought-after link between the heart and the kidney in the control of soduim balance. Pharmacological targeting of the natruiretic peptide system is now leading to novel advances in the treatment of hypertension and of heart failure - two of the most common causes of human disability and death.     

Pronatriuretic peptide is a sensitive marker of the endocrine function of teleost heart

We recently characterized a novel heart-specific hormone from salmon (salmon cardiac peptide, sCP). We have now prepared a recombinant plasmid expressing the NH(2)-terminal fragment of pro-sCP (NT-pro-sCP) and used it to set up a specific RIA for the peptide. Because of the sensitivity of the assay and the high circulating levels, NT-pro-sCP can be measured from as little as 2 microl of serum. This enables repeated sampling from the same animal in different experimental setups. Mechanical load increased the release of NT-pro-sCP from isolated perfused salmon ventricle, in parallel with sCP. Bolus injection of human endothelin-1 (ET-1; 1 microg) in the dorsal aorta of salmon resulted in an extensive increase of serum NT-pro-sCP (from 0.99 +/- 0.11 to 4.6 +/-1.5 nmol/l). The response was abolished by pretreatment with a specific type A ET (ET(A)) receptor antagonist (BQ-123) but not with a type B ET receptor antagonist (BQ-788). The NT-pro-sCP levels had a good correlation with those of sCP (r(2) = 0.75). Our results demonstrate the practical usefulness of circulating NT-pro-sCP as a marker of the endocrine function of salmon heart. They also suggest that ET-1 has an important role in regulating sCP release from teleost heart by an ET(A) receptor-mediated mechanism.     

骨骼肌的内分泌功能

长期以来,骨骼肌被认为是一种效应器官,接受神经和体液的调节。近年大量实验研究资料发现骨骼肌也具有分泌活性物质的功能,能表达、合成和分泌多种生物信号分子,包括调节肽、细胞因子和生长因子等,也是一种重要的内分泌器官。骨骼肌分泌的活性物质以旁分泌和／或自分泌方式调节骨骼肌的生长、代谢和运动功能;甚至以血液循环内分泌的方式调节机体远隔器官组织的功能。骨骼肌生成和分泌的活性物质在运动系统疾病和某些全身性疾病的发病中具有重要的作用。本文将对骨骼肌分泌的主要活性物质及其生理和病理生理学意义进行综述。