GRK mythology: G-protein receptor kinases in cardiovascular disease

G-protein receptor kinases (GRKs) are indispensable for terminating signaling of G-protein coupled receptors (GPCR) through receptor desensitization and downregulation. Increased neurohormone levels in heart failure and the adverse consequences of constant neurohormonal stimulation suggest an important protective role for mechanisms that desensitize neurohormone receptor responses. For that reason, GRK2, the first GRK identified in the heart, has been extensively studied in heart failure, cardiac hypertrophy, and myocardial infarction. However, our understanding of the roles of GRKs in general, and the differential effects of cardiac receptor phosphorylation by individual cardiac-expressed GRKs, have evolved considerably in the last few years. Here, recent developments are reviewed, with an emphasis on novel GRK functions and signaling pathways.     

Scanning mutagenesis reveals a role for serine 189 of the heterotrimeric G-protein beta 1 subunit in the inhibition of N-type calcium channels

Direct interactions between the presynaptic N-type calcium channel and the beta subunit of the heterotrimeric G-protein complex cause voltage-dependent inhibition of N-type channel activity, crucially influencing neurotransmitter release and contributing to analgesia caused by opioid drugs. Previous work using chimeras of the G-protein beta subtypes Gbeta1 and Gbeta5 identified two 20-amino acid stretches of structurally contiguous residues on the Gbeta1 subunit as critical for inhibition of the N-type channel. To identify key modulation determinants within these two structural regions, we performed scanning mutagenesis in which individual residues of the Gbeta1 subunit were replaced by corresponding Gbeta5 residues. Our results show that Gbeta1 residue Ser189 is critical for N-type calcium channel modulation, whereas none of the other Gbeta1 mutations caused statistically significant effects on the ability of Gbeta1 to inhibit N-type channels. Structural modeling shows residue 189 is surface exposed, consistent with the idea that it may form a direct contact with the N-type calcium channel alpha1 subunit during binding interactions.     

Accessory glands in the reproductive system of the male insect

Males of insects and ticks influenced the physiology of reproduction of mated females with the secretes of accessory sexual glands (aD) much more than was supposed in the past. The monocoitic behaviour of the females of some species of insects is caused by various secretions (e.g. Matrone in mosquitoes, monogamic factors in the house fly, sexpeptides in Drosophila). Furthermore the preoviposition period is shortened by these secretions whereas the productivity is increased. The food uptake and the autogeny were influenced as well. Besides this other patterns of behaviour changed (e. g. flight activity). Because of their simple structure, the accessory glands are suitable for biochemical investigations. However, in most cases the physiological functions are unknown.--The present knowledge on the functions of the accessory glands is reviewed with special regard to the modes of action of secretions of the accessory glands.     

Amyloid in the cardiovascular system: a review

The cardiovascular system is a common target of amyloidosis. This review presents the current clinical and diagnostic approach to amyloidosis, with the emphasis on cardiovascular involvement. It summarises recent nomenclature, classification, and pathogenesis of amyloidosis. In addition, non-invasive possibilities are discussed, together with endomyocardial biopsies in the diagnosis of cardiac amyloidosis. Finally, recent advances in treatment and prognostic implications are presented.     

Accessory proteins that control the assembly of MHC molecules with peptides

The stable assembly of Major Histocompatibility Complex (MHC) molecules with peptides is controlled by a number of cofactors, including proteins with general housekeeping functions and proteins with dedicated functions in MHC assembly. Recent work in my laboratory has focused on two chaperones, tapasin (tpn) and DM, that play critical roles in the loading of peptides onto MHC class I and MHC class II molecules, respectively. Tapasin is a transmembrane protein that tethers empty class I molecules in the endoplasmic reticulum to the transporter associated with antigen processing. DM is a peptide exchange factor that binds with empty and peptide-loaded class II molecules in endosomal and lysosomal compartments. Although a number of different functions for tapasin and DM have been proposed, emerging evidence suggests that both of these chaperones retain unstable MHC molecules in peptide-loading compartments until they bind with high-affinity peptides. These cofactors therefore promote the surface expression of long-lived MHC-peptide complexes.     

CaMKII in the cardiovascular system: sensing redox states

The multifunctional Ca(2+)- and calmodulin-dependent protein kinase II (CaMKII) is now recognized to play a central role in pathological events in the cardiovascular system. CaMKII has diverse downstream targets that promote vascular disease, heart failure, and arrhythmias, so improved understanding of CaMKII signaling has the potential to lead to new therapies for cardiovascular disease. CaMKII is a multimeric serine-threonine kinase that is initially activated by binding calcified calmodulin (Ca(2+)/CaM). Under conditions of sustained exposure to elevated Ca(2+)/CaM, CaMKII transitions into a Ca(2+)/CaM-autonomous enzyme by two distinct but parallel processes. Autophosphorylation of threonine-287 in the CaMKII regulatory domain "traps" CaMKII into an open configuration even after Ca(2+)/CaM unbinding. More recently, our group identified a pair of methionines (281/282) in the CaMKII regulatory domain that undergo a partially reversible oxidation which, like autophosphorylation, prevents CaMKII from inactivating after Ca(2+)/CaM unbinding. Here we review roles of CaMKII in cardiovascular disease with an eye to understanding how CaMKII may act as a transduction signal to connect pro-oxidant conditions into specific downstream pathological effects that are relevant to rare and common forms of cardiovascular disease.     

心血管系统的雌激素受体

雌激素对心血管系统的保护作用除了对血脂代谢的改善以外 ,主要来自于雌激素对心血管系统的直接作用。雌激素对靶细胞的特异性作用主要通过基因组效应和非基因组效应完成。具有功能活性的雌激素受体广泛存在于心血管系统     

Accessory proteins and the assembly of human class I MHC molecules: a molecular and structural perspective

The cell-surface presentation of antigenic peptides by class I major histocompatibility complex (MHC) molecules to CD8+ T-cell receptors is part of an immune surveillance mechanism aimed at detecting foreign antigens. This process is initiated in the endoplasmic reticulum (ER) with the folding and assembly of class I MHC molecules which are then transported to the cell surface via the secretory pathway. In recent years, several accessory proteins have been identified as key components of the class I maturation process in the ER. These proteins include the lectin chaperones calnexin (CNX) and calreticulin (CRT), the thiol-dependent oxidoreductase ERp57, the transporter associated with antigen processing (TAP), and the protein tapasin. This review presents the most recent advances made in characterizing the biochemical and structural properties of these proteins, and discusses how this knowledge advances our current understanding of the molecular events underlying the folding and assembly of human class I MHC molecules in the ER.     

Fractal model for blood flow in cardiovascular system

Blood flow in the cardiovascular system is the central point of experimental and theoretical investigation. The objective of the study is to determine the blood flow in the cardiovascular system using Darcy's law, Reynold's number and Poiseuille's equation. A possible way of modeling of self-similar biological tree-like structure is proposed. Special attention is paid to the blood vessel system, with elaboration on a model with certain spatial arrangement of the vessels and reasonable dependence of the blood pressure on the vessels diameter such that the organism has a homogeneous oxygen supply. Flow analysis in the above systems is analyzed by invasion percolation. The blood flow in the cardiovascular system has been numerically calculated for both normal and abnormal patients. A new algorithm has been introduced to visit the blood vessels in a robust manner which avoids loops and provides us the results in a simple manner.     

Allergy and the cardiovascular system

The most dangerous and life-threatening manifestation of allergic diseases is anaphylaxis, a condition in which the cardiovascular system is responsible for the majority of clinical symptoms and for potentially fatal outcome. The heart is both a source and a target of chemical mediators released during allergic reactions. Mast cells are abundant in the human heart, where they are located predominantly around the adventitia of large coronary arteries and in close contact with the small intramural vessels. Cardiac mast cells can be activated by a variety of stimuli including allergens, complement factors, general anesthetics and muscle relaxants. Mediators released from immunologically activated human heart mast cells strongly influence ventricular function, cardiac rhythm and coronary artery tone. Histamine, cysteinyl leukotrienes and platelet-activating factor (PAF) exert negative inotropic effects and induce myocardial depression that contribute significantly to the pathogenesis of anaphylactic shock. Moreover, cardiac mast cells release chymase and renin that activates the angiotensin system locally, which further induces arteriolar vasoconstriction. The number and density of cardiac mast cells is increased in patients with ischaemic heart disease and dilated cardiomyopathies. This observation may help explain why these conditions are major risk factors for fatal anaphylaxis. A better understanding of the mechanisms involved in cardiac mast cell activation may lead to an improvement in prevention and treatment of systemic anaphylaxis.     

Sphingosine 1 phosphate induces the chemotaxis of human natural killer cells. Role for heterotrimeric G proteins and phosphoinositide 3 kinases

We have examined the effect of sphingolipids on the chemotaxis of human natural killer (NK) cells. Messenger RNA for Edg-1, Edg-6 and Edg-8 but not Edg-3, are expressed in these cells. Sphingosine 1 phosphate (SPP), dihydro SPP (DHSPP) or the CC chemokine RANTES (CCL5), but not sphingosine induces the chemotaxis of these cells. Pertussis toxin inhibits the chemotaxis induced by these ligands. Permeabilization of NK cells with streptolysin O (SLO) and introduction of blocking antibodies to the heterotrimeric G proteins, showed that Galpha(i2), Galpha(s), Galpha(q/11) or Galpha(13) mediate the chemotaxis of SPP, whereas Galpha(i2), Galpha(o) or Galpha(q/11) mediate the chemotaxis of DHSPP. Galpha(i2), Galpha(o), Galpha(s), Galpha(q/11), Galpha(z) or Galpha(12 )mediates RANTES-induced NK cell chemotaxis. Further analysis showed that phosphoinositide 3 kinase (PI3K) inhibitors wortmannin and LY294002 inhibit NK cell chemotaxis induced by SPP, DHSPP or RANTES. Blocking antibody to PI3Kgamma inhibits the chemotaxis induced by the three ligands, whereas anti-PI3Kbeta was without effect. In contrast, SPP and DHSPP recruit PI3Kbeta isozyme into NK cell membranes, suggesting that although this isoform is not involved in chemotaxis, it is activated by these phospholipids.     

Hydrogen sulfide in the mammalian cardiovascular system

For more than a century, hydrogen sulfide (H(2)S) has been regarded as a toxic gas. This review surveys the growing recognition of the role of H(2)S as an endogenous signaling molecule in mammals, with emphasis on its physiological and pathological pathways in the cardiovascular system. In biological fluids, H(2)S gas is a weak acid that exists as about 15% H(2)S, 85% HS(-), and a trace of S(2-). Here, we use "H(2)S" to refer to this mixture. H(2)S has been found to influence heart contractile functions and may serve as a cardioprotectant for treating ischemic heart diseases and heart failure. Alterations of the endogenous H(2)S level have been found in animal models with various pathological conditions such as myocardial ischemia, spontaneous hypertension, and hypoxic pulmonary hypertension. In the vascular system, H(2)S exerts biphasic regulation of a vascular tone with varying effects based on its concentration and in the presence of nitric oxide. Over the past decade, several H(2)S-releasing compounds (NaHS, Na(2)S, GYY4137, etc.) have been utilized to test the effect of exogenous H(2)S under different physiological and pathological situations in vivo and in vitro. H(2)S has been found to promote angiogenesis and to protect against atherosclerosis and hypertension, while excess H(2)S may promote inflammation in septic or hemorrhagic shock. H(2)S-releasing compounds and inhibitors of H(2)S synthesis hold promise in alleviating specific disease conditions. This comprehensive review covers in detail the effects of H(2)S on the cardiovascular system, especially in disease situations, and also the various underlying mechanisms.     

Nitric oxide in the cardiovascular system: its role in adaptive protection

Nitric oxide (NO) is involved virtually in all processes occurring in the body. In the cardiovascular system, it regulates cardiac contractility, blood coagulability, cell proliferation, vascular tone, and blood pressure (BP). NO deficiency leads to the development of severe cardiovascular diseases associated with endothelial dysfunction, abnormally increased vascular tone and BP (such as hypertension, angina pectoris, atherosclerosis, diabetic angiopathy, etc.) At the same time, NO hyperproduction makes a contribution to the development of septic, cardiogenic, thermal, and other shocks. The most effective non-drug stimulation of NO synthesis is a gradual adaptation to environmental factors. The adaptation-induced elevation of NO levels, followed by vascular wall NO deposition, on the one hand, limits the damaging action of excess NO in shocks by the feedback, and, on the other, makes up some NO reserve which may be used in NO deficiency. Further studies of NO-dependent adaptive mechanisms will allow the agent to be used in the prevention and treatment of cardiovascular diseases associated with NO metabolic disturbances.     

Infectious diseases of the cardiovascular system

Infection and inflammation of the cardiovascular system are a frequent cause of cardiac and/or vascular disease. Major advances have now occurred in understanding cellular and molecular bases of a wide variety of inflammatory cardiovascular diseases. Some of these (myocarditis) have been recognized as inflammatory disease for a long time. In others such as atherosclerosis, the inflammatory nature of the disease has emerged only recently. Myocarditis and pericarditis are inflammation of specific layers of the heart. Myocarditis can lead to heart failure or arrhythmia, and myocytes or the conductive system can be affected. Pericarditis often presents with pain, ever and friction rub, sometimes with malaise or weight loss. Infective endocarditis affects usually the cardiac valves and can be fatal if not treated. Acute or chronic, mostly bacterial in origin, though fungal infections are becoming more common. While diseased valves as a cause is decreasing, medical interventions and immunosuppression as well as prosthetic valves are resulting in an increase in endocarditis. Organisms can enter from oral cavity, especially if there is poor dental hygiene or when dental work has taken place. Vasculitis can also be caused by infections but is very rare.