【III】 国 際 学 会
1）Matsuda N，Mayumi T，Kemmotsu O
Propofol and vecuronium for crash induction.
2nd Asia-Osean Society of Intravenous Anesthesia，Feb 1998，Kyoto
2）Matsuda N，Gando S，Hattori Y，Suzuki Y，Kemmotsu O
Involvement of altered G protein in the attenuation of the positive inotropic response to β-adrenoceptor stimulation in myocardium from septic rabbits.
1999 The American Society of Anesthesiologists Annual Meeting，Oct 1999，Dallas
3）Matsuda N，Hattori Y，Kemmotsu O，Gando S
Pathological significant of over-expression of histamine and altered transcriptional regulation of H1- and H2-receptor during septic shock.
International Sendai Histamine Symposium，Nov 22-25，2000，Sendai
4）Matsuda N， Hattori Y，Gando S，Kemmotsu O
Alterations in endogenous histamine production and histamine receptor density at transcriptional levels are related to hemodynamic changes during septic shock.
2000 The American Society of Anesthesiologists Annual Meeting，Oct 2000，San Francisco
5）Matsuda N， Hattori Y， Gando S，Kemmotsu O
Increased vascular permeability by up-regulation of histamine H1 receptor and L-histidine decarboxylase in endotoxemic rabbits.
2001 The American Society of Anesthesiologists Annual Meeting，Oct 2001，New Orleans
6）Matsuda N，Gando S，Kemmotsu O
Hemodynamic significance of histamine synthesis and gene expression during septic shock.
The 2nd Joint Congress of Korean-Japanese Intensivists，March 2002，Okayama
7）Matsuda N， Jesmin S，Sakuma I，Kemmotsu O，Gando S， Hattori Y
Expression of vascular endothelial growth factor and its receptors are reduced in parallel with endothelial nitric oxide synthase expression in endotoxemia.
12th International Vascular Biology Meeting，May 12-16，2002，Karuizawa
8）Matsuda N，Hattori Y，Gando S， Kemmotsu O
Gene transfection of NF-kB decoy oligonucleotides improves transcriptional regulation of NO synthase，vascular endothelial growth factor and histamine H1 receptor in septic mouse lung: potential therapeutic strategy for accelerated lung vascular permeability in sepsis.
2002 The American Society of Anesthesiologists Annual Meeting，October 12-16，2002，Orlando
9）Yagasaki K， Gando S， Matsuda N， Iseki K
Pharmaco kinetics and the most suitable dosing regimen of fluconazole in critically ill pateits receiving continuous hemodiafltration.
Toronto Critical Care Medicine Symposium，Nov 2002，Toronto
10）Gando S， Kameue T， Morimoto Y， Matsuda N， Kemmotsu O
Marked reductions of protein C and antithrombin in post-trauma DIC have close relations with MODS and poor outcome.
22nd International Symposium on Intensive Care and Emergency Medicine，March 2002，Brussels
11）Matsuda N，Gando S，Kemmotsu O，Hattori Y
Gene transfection of NF-kB decoy oligonucleotides improves vascular permeability in septic mouse lung.
International Society for Heart Research 19th Annual Meeting，Oct 31-Nov 2，2003，Yamagata
12）Matsuda N，Hattori Y，Gando S，Kemmotsu O
Gene transfection of NF-kB decoy oligonucleotides improves transcriptional regulation of bradykinin receptors， NO synthase and histamine H1 receptor in septic mouse lung: potential therapeutic strategy for accelerated lung vascular permeability in septic ARDS.
Association of University Anesthesiologists 50th Annual Meeting，May 2-4 2003， Milwaukee
13）Matsuda N， Hattori Y，Gando S，Kemmotsu O
Inhalational gene transfection of NF-kB decoy oligonucleotides strongly improves vascular permeability by inhibition of transcriptional up-regulation of bradykinin B1 and B2 receptors，histamine H1 receptor，inducible NO synthase and cyclooxygenase 2 in septic mouse lung.
The 2nd Joint Congress of Korean-Japanese Intensivist Symposium，May 31 2003，Yokohama
14）Gando S，Kameue T，Matsuda N，Hayakawa M，Hoshino H
DIC and systemic inflammation interactions in sepsis contribute to MODS and poor outcome.
European Society of Intencive cone Medicine 2003 Oct 2003，Amsterdam
15）Matsuda N，Nishihira J，Hattori Y，Gando S
Macrophage migration inhibitory factor is a key regulator of septic second attack in pancreatitis.
The 3rd Joint Scientific Congress of Korean-Japanese Intensivist Symposium，Nov 14-16，2003，Seoul
16）Matsuda N，Hattori Y，Jesmin S，Gando S
Diminished phosphatidylinositol 3-kinase/Akt-dependent phosphorylation of endothelial nitric oxide synthase in endotoxemic rabbits.
International Society for Heart Resarch 20th Annual Meeting，Nov 22-26，2003，Tokyo
17）Matsuda N，Hattori Y，Gando S，Kemmotsu O
Inhaled gene transfection of NF-kB decoy oligonucleotides improves lung vascular permeability in septic mice.
Society of Critical Care Medicine 33rd Critical Care Congress，Feb 19-25，2004，Orlando，Florida
18）Matsuda N，Nishihira J，Hattori Y，Gando S
Pancreatitis upregulates Toll-like receptor 4 gene expression in mouse kidney by macrophage migration inhibitory factor.
Society of Critical Care Medicine 33rd Critical Care Congress Feb 19-25，2004，Orlando
19）Matsuda N，Gando S
Reversal effects of fuluvastatin on decreased phosphorylation of endothelial nitric oxide synthase in the mesenteric artery of endotoxemic rabbits.
The 4th Joint Scientific Congress of Korean-Japanese Intensivist Symposium，March 6，2004，Fukuoka
20）Matsuda N，Nishihira J，Hattori Y，Gando S，Kemmotsu O
MIF enhances infectious second attack via up-regulation of Toll-like receptor 4 in the lung of pancreatitis mouse.
Association of University Anesthesiologists 51th Annual Meeting，May 13-15，2004，Sacramento
21）Gando S，Jesmin S，Sakuma I，Kobayahi S，Sakuraya F，Matsuda N，Hattori Y.
Increased pulmonary expression of thrombin receptor in rabbits with endotoxin-induced acute lung injury.
18th International Congress on Thrombosis June，2004，Ljublijana Slovenia
22）Matsuda N，Hattori Y.
Histamine H1 and H2 receptor expression in the hearts of rodents and humans.
9th International Congress of Cardiothoracic and Vascular Anesthesia，Sep 9-12，2004，Tokyo
23）Matsuda N，Nishihira J，Hattori Y，Gando S，Kemmotsu O.
Molecular mechanism for the development of acute lung injury in mice with pancreatitis.
2004 Annual Meeting of American Society of Anesthesiologysts
October 23-27，2004，Las Vegas
24）Matsuda N，Hattori Y.
Regulatory role of macrophage migration inhibitory factor (MIF) in cardiac histamine synthesis in endotoxemic mice.
International Society for Heart Research 21th Annual Meeting，Nov 24-25，2004，Yamanashi
25）Matsuda N，Hattori Y，Takahashi Y，Gando S，Kemmotsu O.
AP-1 decoy oligonucleotides can improve acute lung injury by suppressing up-regulation of inflammatory receptors and enzymes in septic mice.
Society of Critical Care Medicine 34th Critical Care Congress Jan 15-18，2005，Phoenix
26）Matsuda N，Hattori Y，Gando S，Kemmotsu O.
Olprinon normalizes eNOS phosphorylation via up-regulation of VEGF and HGF in mesenteric arteries from endotoxemic rabbits.
Society of Critical Care Medicine 34th Critical Care Congress Jan 15-18，2005，Phoenix
27）Gando S，Kameue T，Matsuda N，Sawamura A，Hayakawa M.
Systemic inflammation and DIC in early stage of ALI and ARDS: role of neutrofhil and endothelial activation.
Society of Critical Care Medicine 34th Critical Care Congress Jan 15-18，2005，Phoenix
28）Matsuda N，Hattori Y， Takahashi Y，Gando S.
Prevention of sepsis-induced acute lung injury by small interfering RNA for inhibition of tissue factor expression.
Society of Critical Care Medicine 34th Critical Care Congress Jan，7-11 2006，San Francisco，CA
29）Matsuda N，Hattori Y，Takahashi Y，Gando S，Kemmotsu O.
Sepsis-induced changes in the signaling mechanisms for glucose transport 4 translocation to the membrane.
Society of Critical Care Medicine 34th Critical Care Congress Jan，7-11 2006，San Francisco，CA
30）Gando S，Matsuda N，Sawamura A，Hayakawa M.
High macrophage migration inhibitory factor levels in disseminated intravascular coagulation patients with septic inflammatory response syndrome and sepsis.
Society of Critical Care Medicine 34th Critical Care Congress Jan，7-11 2006，San Francisco，CA
31) Matsuda N.
Altered signaling transduction of glucose transport 4 translocation to the membrane in sepsis-induced hyperglycemia.
The 6th Joint Scientific Congress of Korean-Japanese Intensivist Symposium，2 March ，2006，Osaka
32）Matsuda N，Gando S.
siRNA targeting caspase-3 and -8 prevents endothelial cell derangements in septic mice.
Europian Society of Intensive Care Medicine 19th Annual Congress Sep 24-27，2006，Barcelona
33）Matsuda N，Yamazaki Y，Hattori Y.
Pro-apoptotic gene silencing in septic mouse aorta by small interfering RNA.
2006 Annual Meeting of American Society of Anesthesiologysts the Special ASCCA/Journal Session.
October 16，2006，Chicago
34）Matsuda N，Yamazaki Y，Hattori Y.
Reversal effects of fluvastatin on Akt activity in the mesenteric artery of septic rabbits.
2006 Annual Meeting of American Society of Anesthesiologysts
October 15，2006，Chicago
35) Hama K，Kinoshita H，Matsuda N，Tohyama S，Hatano Y.
Sevoflurane but not propofol inhibits activity of Rho kinase in the porcine coronary artery.
2006 Annual Meeting of American Society of Anesthesiologysts
October 15，2006，Chicago
36) Kamiyama K，Matsuda N，Nagata T，Tsukada K，Hattori Y.
Cardiac expression of glucocorticoid receptor α in mice.
International Society for Heart Resarch 23th Annual Meeting，Dec 1-2，2006，Chiba
37）Yamamoto S, Muramatsu M, Osawa T, Sagara H, Murakami M, Takahashi H, Matsuda N, Hattori Y, Niida S, Shibuya M.
Pericyte recruitment during the neurogenesis period of the central nervous system.
NAVBO, Developmental Vascular Biology Workshop III, Jan 2008, California
【III】 国 際 学 会
続き
38）Hatakeyama N, Matsuda N, Aoki Y, Hattori Y, Yamazaki M.
Mechanism of tachyarrhythmia in septic guinea pig atrial myocyte.
Society of critical Care Medicine 37th Critical Care Congress, Feb 2-6, 2008，Honolulu
39）Matsuda N, Koike K, Kageyama SI, Yamamoto S, Hatakeyama N, Takano Y, Hattori Y.
Gene silencing of FADD with small interfering RNA improves septic survival by prevention of apoptosis in main organs.
Society of critical Care Medicine 37th Critical Care Congress, Feb 2-6, 2008，Honolulu
40）Matsuda N, Koike K
Gene silencing of FADD with small interfering RNA for severe sepsis.
Trauma Care 2008, Jun 12-13, 2008, Tokyo
41）Hatakeyama N, Matsuda N, Aoki Y, Yamada M, Yamazaki M.
Involvement of Na + channel in the mechanism of tachyarrhythmia in septic guinea pig atrial myocyte.
2008 Annual Meeting of American Society of Anesthesiologysts, Oct 18-22, 2008, Orlando
42）Kinoshita H, Matsuda N, Azuma T, Hatakeyama N, Hatano Y.
The role of PI3K-Akt in human vascular ATP-sensitive K + channel function modified by high glucose.
2008 Annual Meeting of American Society of Anesthesiologysts, Oct 18-22, 2008, Orlando
43）Haba M, Kinoshita H, Azuma T, Matsuda N, Hatano Y.
The role of oxidative stress in vascular ATP-sensitive K + channel function and the effect of propofol.
2008 Annual Meeting of American Society of Anesthesiologysts, Oct 18-22, 2008, Orlando
44）Tange K, Kinoshita H, Matsuda N, Hatakeyama N, Hatano Y.
Expansion of fluid containers by warming and the changes in fluid temperature during rapid infusion.
2008 Annual Meeting of American Society of Anesthesiologysts, Oct 18-22, 2008, Orlando
45）Kageyama S, Matsuda N, Kageyama N, Yamamoto S, Takano K, Fukuoka J, Yokoo H, Hattori Y.
Up-regulation of death receptors contributes to high glucose-induced apoptosis in human coronary artery endothelial cells.
The 6th Korea-Japan Joint Symposium on Vascular Biology and The 16th Annual Meeting of the Japan Vascular Biology and Medicine Organization joint meeting, Dec 3-5, 2008, kanazawa
46）Yamamoto S, Muramatsu M, Koo B, Mukouyama Y, Osawa T, Sagara H, Takahashi H, Takano K, Urakabe S, Niida S, Shibuya M, Matsuda N, Hattori Y.
Hematopoietic cells generate pericytes and contribute the CNS vasculature during development.
The 6th Korea-Japan Joint Symposium on Vascular Biology and The 16th Annual Meeting of the Japan Vascular Biology and Medicine Organization joint meeting, Dec 3-5, 2008, kanazawa
47）Urakabe S, Yamamoto S, Takano K, Yokoo H, Ikutani M, Nagai Y, Takatsu K, Matsuda N, Hattori Y.
Yolk sac derived progenitor cells form cell clusters and differentiate into endothelial cells and smooth muscle cells.
The 16th Korea-Japan Joint Symposium on Vascular Biology and The 16th Annual Meeting of the Japan Vascular Biology and Medicine Organization joint meeting, Dec 3-5, 2008, kanazawa
48）Matsuda N, Hattori Y, Yamamoto S, Yamazaki H, Koike K.
Impact of transcription factor decoy to AP-1 on the Lung apoptosis of septic mice.
Society of critical Care Medicine 38th Critical Care Congress, Jan 31-Feb 4, 2009，Nashville
49）Matsuda N, Hattori Y, Hatakeyama N, Koike K.
Acute lung inflammation induced by blood stream infection of candida glabrata in mice.
Society of critical Care Medicine 38th Critical Care Congress, Jan 31-Feb 4, 2009，Nashville
50）Matsuda N, Hattori Y, Hatakeyama N, Yamazaki M, Koike K.
Fluid resuscitation in rabbits with endotoxemic shock: Impact on regulation of NF-κB activation and production of inflammatory molecules.
Society of critical Care Medicine 38th Critical Care Congress, Jan 31-Feb 4, 2009，Nashville
51）Hatakeyama N, Matsuda N, Yamamoto S, Aoki Y, Hattori Y, Yamazaki M.
Involvement of Ca2＋ and Na＋ Channels in the mechanism of tachyarrhythmia in septic guinera pig atrium.
Society of Critical Care Medicine 38th Critical Care Congress, Jan 31-Feb 4, 2009，Nashville
52）Matsuda N.
2009 Review
Basic science of cardiovascular imflammation: effects of opioids and catecholamines for inflammatory action of leukocytes.
The 8th meeting of the Asian Society of Cardiothoracic Anesthesia, Sep 11, 2009, Tokyo
53）Matsuda N, Hattori Y, Yamamoto S, Teramae H, Koike K.
Inhaled TAK1 siRNA improves lung inflammation and apoptosis by reducing transcriptional activity of NF-κB and AP-1 in septic mice.
Society of Critical Care Medicine 39th Critical Care Congress, Jan 9-13, 2010，Miami
54）Suzuki T, Matsuda N, Teramae H, Beppu S, Futatsugi M, Koike K.
Implication of endoplasmic reticulam stress in pancreas in the patophysiology of sepsis.
Society of Critical Care Medicine 39th Critical Care Congress, Jan 9-13, 2010，Miami
55）Hatakeyama N, Aoki Y, Matsuda N, Kinoshita H, Yamazaki M.
Tachyarrhythmia in sepsis is attributable to both the inhibition of calcium channel expression and nitrotyrosilation of calkcium channel.
Society of Critical Care Medicine 39th Critical Care Congress, Jan 9-13, 2010，Miami
56）Matsuda N.
Symposium on Organ Failure in ICU
Current Insight into Endothelial Dysfunction with Septic Inflammation
13th Asian Australasian Congress of Anesthesiologists Jun 3, 2010, Hakata
57）Matsuda N and Teramae H.
FADD siRNA reduces autophagy and apoptosis in septic mice.
Society of Critical Care Medicine 40th Critical Care Congress, Jan 15-19, 2010，San Diego
Standaert ML, Sajan MP, Miura A, Bandyopadhyay G, Farese RV.
Research Service, James A. Haley Veterans Medical Center, and Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612, USA.
Cbl is phosphorylated by the insulin receptor and reportedly functions within the flotillin/CAP/Cbl/Crk/C3G/TC10 complex during insulin-stimulated glucose transport in 3T3/L1 adipocytes. Cbl, via pYXXM motifs at tyrosine-371 and tyrosine-731, also activates phosphatidylinositol (PI) 3-kinase, which is required to activate atypical protein kinase C (aPKC) and glucose transport during thiazolidinedione action in 3T3/L1 and human adipocytes [Miura et al. (2003) Biochemistry 42, 14335-14341]. Presently, we have examined the importance of Cbl in activating PI 3-kinase and aPKC during insulin action in 3T3/L1 adipocytes by expressing Y371F and Y731F Cbl mutants, which nullify pYXXM binding of Cbl to SH2 domains of downstream effectors. Interestingly, these mutants inhibited insulin-induced increases in (a) binding of Cbl to both Crk and the p85 subunit of PI 3-kinase, (b) activation of Cbl-dependent PI 3-kinase, (c) activation and translocation of aPKC to the plasma membrane, (d) translocation of Glut4 to the plasma membrane, (e) and glucose transport. Importantly, coexpression of wild-type Cbl reversed the inhibitory effects of Cbl mutants. In contrast to Cbl-dependent PI 3-kinase, Cbl mutants did not significantly inhibit the activation of PI 3-kinase by IRS-1, which is also required during insulin action. Our findings suggest that (a) Cbl uses pYXXM motifs to simultaneously activate PI 3-kinase and Crk/C3G/TC10 pathways and (b) Cbl, along with IRS-1, functions upstream of PI 3-kinase and aPKCs during insulin-stimulated glucose transport in 3T3/L1 adipocytes.
すこしマニアックですが，最近の僕の研究テーマですので，のせておきます。
Shian-Huey Chiang1,2, Christian A. Baumann2,3, Makoto Kanzaki4, Debbie C. Thurmond4, Robert T. Watson4, Cheryl L. Neudauer5, Ian G. Macara5, Jeffrey E. Pessin4and Alan R. Saltiel2,3
Top of page筋肉や脂肪組織でインスリンによってグルコース取込みが促進されるには,グルコース輸送タンパク質GLUT4が細胞内の貯蔵部位から細胞表面へと移行する必要がある。GLUT4小胞の細胞内移動は詳しく解明されているが，インスリン受容体とGLUT4移行とを結びつける情報伝達経路についてはほとんどわかっていない。GLUT4移行にはホスファチジルイノシトール‐3‐OHキナーゼ（PI(3)K）の活性化が必要だが，それだけではGLUT4移行は起こらない。我々はこれまでに，インスリン刺激によるCblのチロシンリン酸化がかかわる経路を報告した。Cblはアダプタータンパク質CAPによってインスリン受容体へと運ばれる。Cblはリン酸化されると細胞膜の脂質微小領域へと移行するが，この移行を妨げると，インスリンによるGLUT4移行の促進が完全に阻害された。ここでは，リン酸化されたCblの働きでCrkII-C3G複合体が脂質微小領域へ移行し，そこでC3Gが低分子量GTP結合タンパク質TC10を特異的に活性化することを明らかにする。この過程にはPI(3)Kは無関係だが，CblとCrk，C3Gの脂質微小領域への移行は必要である。インスリン刺激によるグルコース取込みの促進とGLUT4の移行には，このTC10の活性化が不可欠である。このTC10経路は，PI(3)K経路と並行して，インスリンによるGLUT4の移行を促進する働きをしている
Kenneth Feingold, Min Sun Kim, Judy Shigenaga, Art Moser, and Carl Grunfeld
Metabolism Section, Department of Medicine, University of California San Francisco, Medical Service, Department of Veterans Affairs Medical Center, San Francisco, California 94121
Severe sepsis results in the decreased uptake and oxidation of fatty acids in the heart and cardiac failure. Some of the key proteins required for fatty acid uptake and oxidation in the heart have been shown to be downregulated after endotoxin (LPS) administration. The nuclear hormone receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid receptor (TR), which heterodimerize with the retinoid X receptor (RXR), are important regulators of fatty acid metabolism and decrease in the liver after LPS administration. In the present study, we demonstrate that LPS treatment produces a rapid and marked decrease in the mRNA levels of all three RXR isoforms, PPAR and PPAR, and TR and TR in the heart. Moreover, LPS administration also decreased the expression of the coactivators CREB-binding protein (CBP)/p300, steroid receptor coactivator (SRC)-1, SRC-3, TR-associated protein (TRAP)220, and PPAR coactivator (PGC)-1, all of which are required for the transcriptional activity of RXR-PPAR and RXR-TR. In addition, the mRNA levels of the target genes malic enzyme, Spot 14, sarcoplasmic reticulum Ca2+-ATPase, or SERCA2, the VLDL receptor, fatty acyl-CoA synthetase, fatty acid transporter/CD36, carnitine palmitoyltransferase I, and lipoprotein lipase decrease in the heart after LPS treatment. The decrease in expression of RXR, -, and -, PPAR and -, and TR and -, and of the coactivators CBP/p300, SRC-1, SRC-3, TRAP220, and PGC-1 and the genes they regulate, induced by LPS in the heart, could account for the decreased expression of key proteins required for fatty acid oxidation and thereby play an important role in cardiac contractility. These alterations could contribute to the myocardial dysfunction that occurs during sepsis.
Luke A J O'Neill
オニールもたいしたものだ。
Toll-like receptors act as mediators of injury or repair in the inflamed lung, and the balance depends on the integrity of a component of the extracellular matrix (pages 1173–1179).
現時点ではオニールと結託すると，僕のデータもグレードアップして，かなりすごい論文がいくつも出せそうに思われる。僕の秘策はまだまだあるのだ。だが時間がない。時間がないことに一番困っている。とにかく，瑣末なことを取り除き，仕事だけに専念させていただきたい毎日である。
僕の実験でも当たり前のことしかデータに出ていないが
Nature Medicineにでるということはすごい。
Alert cell starategyを早くまとめたいものです。
Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88-/- and Tlr4-/-Tlr2-/- mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell–specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell–surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-B. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.
Fadi G. Akar, Miguel A. Aon, Gordon F. Tomaselli and Brian O’Rourke
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Brian O’Rourke, Division of Cardiology, Johns Hopkins University, 720 Rutland Avenue, Ross 844, Baltimore, Maryland 21205, USA. Phone: (410) 614-0034; Fax: (410) 955-7953; E-mail: bor@jhmi.edu.
Recovery of the mitochondrial inner membrane potential (m) is a key determinant of postischemic functional recovery of the heart. Mitochondrial ROS-induced ROS release causes the collapse of m and the destabilization of the action potential (AP) through a mechanism involving a mitochondrial inner membrane anion channel (IMAC) modulated by the mitochondrial benzodiazepine receptor (mBzR). Here, we test the hypothesis that this mechanism contributes to spatiotemporal heterogeneity of m during ischemia-reperfusion (IR), thereby promoting abnormal electrical activation and arrhythmias in the whole heart. High-resolution optical AP mapping was performed in perfused guinea pig hearts subjected to 30 minutes of global ischemia followed by reperfusion. Typical electrophysiological responses, including progressive AP shortening followed by membrane inexcitablity in ischemia and ventricular fibrillation upon reperfusion, were observed in control hearts. These responses were reduced or eliminated by treatment with the mBzR antagonist 4'-chlorodiazepam (4'-Cl-DZP), which blocks depolarization of m. When applied throughout the IR protocol, 4'-Cl-DZP blunted AP shortening and prevented reperfusion arrhythmias. Inhibition of ventricular fibrillation was also achieved by bolus infusion of 4'-Cl-DZP just before reperfusion. Conversely, treatment with an agonist of the mBzR that promotes m depolarization exacerbated IR-induced electrophysiological changes and failed to prevent arrhythmias. The effects of these compounds were consistent with their actions on IMAC and m. These findings directly link instability of m to the heterogeneous electrophysiological substrate of the postischemic heart and highlight the mitochondrial membrane as a new therapeutic target for arrhythmia prevention in ischemic heart disease.
Meinrad Gawaz, Harald Langer and Andreas E. May
Meinrad Gawaz, Medizinische Klinik III, Eberhard Karls Universität Tübingen, Otfried-Müller-Straße 10, D-72076 Tübingen, Germany. Phone: 49-7071-29-83688; Fax: 49-7071-29-5749; E-mail: meinrad.gawaz@med.uni-tuebingen.de.
Platelet-derived mediators stimulate inflammation
During the adhesion process, platelets become activated and release an arsenal of potent inflammatory and mitogenic substances into the local microenvironment, thereby altering chemotactic, adhesive, and proteolytic properties of ECs (24). These platelet-induced alterations of the endothelial phenotype support chemotaxis, adhesion, and transmigration of monocytes to the site of inflammation (Figure 2).
Released from dense granules, -granules, lysosomes, the canalicular system, or the cytosol, platelets secrete or expose adhesion proteins (e.g., fibrinogen, fibronectin, vWF, thrombospondin, vitronectin, P-selectin, GPIIb/IIIa), growth factors (e.g., PDGF, TGF-ß, EGF, bFGF), chemokines (e.g., RANTES, platelet factor 4 [CXC chemokine ligand 4], epithelial neutrophil-activating protein 78 [CXC chemokine ligand 5]), cytokine-like factors (e.g., IL-1ß, CD40 ligand, ß-thromboglobulin), and coagulation factors (e.g., factor V, factor XI, PAI-1, plasminogen, protein S). These proteins act in a concerted and finely regulated manner to influence widely differing biological functions such as cell adhesion, cell aggregation, chemotaxis, cell survival and proliferation, coagulation, and proteolysis, all of which accelerate inflammatory processes and cell recruitment. For example, IL-1ß has been identified as a major mediator of platelet-induced activation of ECs (25, 26). The IL-1ß activity expressed by platelets appears to be associated with the platelet surface, and coincubation of ECs with thrombin-activated platelets induces IL-1ß–dependent secretion of IL-6 and IL-8 from ECs (26). Furthermore, incubation of cultured ECs with thrombin-stimulated platelets significantly enhances the secretion of endothelial monocyte chemoattractant protein-1 (MCP-1) in an IL-1ß–dependent manner (12). MCP-1 belongs to the CC family of chemokines and is thought to play a key role in the regulation of monocyte recruitment to inflamed tissue and in atherosclerosis (27, 28).
However, platelet IL-1ß does not only modify endothelial release of chemotactic proteins. IL-1ß additionally can increase endothelial expression of adhesion molecules. Surface expression of ICAM-1 and vß3 on ECs is significantly enhanced by activated platelets via IL-1ß (12). Both enhanced chemokine release and upregulation of endothelial adhesion molecules through platelet-derived IL-1ß act in concert and promote neutrophil and monocyte adhesion to the endothelium. IL-1ß–dependent expression of early inflammatory genes, such as MCP-1 or ICAM-1, involves the activation of the transcription factor NF-B. Transient adhesion of platelets to the endothelium initiates degradation of IB and supports activation of NF-B in ECs, thereby inducing NF-B–dependent chemokine gene transcription (29, 30). Likewise, platelet-induced NF-B activation was largely reduced by IL-1ß antagonists, which supports the notion that platelet IL-1ß is the molecular determinant of platelet-dependent activation of the transcription factor. Activation of NF-B involves a cascade of phosphorylation processes. One family of kinases that is involved in NF-B–dependent gene expression is the MAPKs, such as p38 MAPK. In a manner similar to that of recombinant human IL-1ß, activated platelets have the potential to induce phosphorylation of p38 MAPK. Correspondingly, transfection of a dominant-negative p38 mutant significantly reduced platelet-induced MCP-1 secretion in ECs (31).
Once recruited to the vascular wall, platelets may promote inflammation by chemoattraction of leukocytes through mediators such as platelet-activating factor and macrophage inflammatory protein-1, may stimulate smooth muscle cell proliferation (TGF-ß, PDGF, serotonin) (32), and may contribute to matrix degradation by secretion of MMP-2 (33).
A finely regulated functional interaction of platelets with chemokines has also been implicated in atherogenesis (34). Activated platelets can release chemokines and can induce the secretion of chemokines in various cells of the vascular wall; in turn, certain chemokines can enhance platelet aggregation and adhesion in combination with primary agonists and can trigger monocyte recruitment (35). One such candidate for monocyte recruitment is RANTES, which has been shown to trigger monocyte arrest on inflamed and atherosclerotic endothelium (35). Deposition of platelet-derived RANTES induces monocyte recruitment mediated by P-selectin (36, 37). Another platelet-derived chemokine is platelet factor 4 (PF4), the most abundant protein secreted by activated platelets. First, PF4 acts as a chemoattractant for monocytes promoting their differentiation into macrophages (38). Second, PF4 may directly aggravate the atherogenic actions of hypercholesterolemia by promoting the retention of lipoproteins. Sachais and colleagues have recently shown that PF4 can facilitate the retention of LDL on cell surfaces by inhibition of its degradation by the LDL receptor (39). In addition, PF4 markedly enhances the esterification and uptake of oxidized LDL by macrophages (40). The fact that PF4 has been found in human atherosclerotic lesions and was found associated with macrophages in early lesions and with foam cells in more advanced lesions (41) supports the concept that PF4 released from locally activated platelets enters the vessel wall and promotes vascular inflammation and atherogenesis.
Furthermore, release of platelet-derived CD40 ligand (CD40L, CD154) induces inflammatory responses in endothelium. Henn et al. (42) showed that platelets store CD40L in high amounts and release it within seconds after activation in vitro. Ligation of CD40 on ECs by CD40L expressed on the surface of activated platelets increased the release of IL-8 and MCP-1, the principal chemoattractants for neutrophils and monocytes (42). In addition, platelet CD40L enhanced the expression of endothelial adhesion receptors including E-selectin, VCAM-1, and ICAM-1, all molecules that mediate the attachment of neutrophils, monocytes, and lymphocytes to the inflamed vessel wall (42). Moreover, CD40L induces endothelial tissue factor expression (43). Hence, like IL-1ß, CD40L expressed on platelets induces ECs to release chemokines and to express adhesion molecules, thereby generating signals for the recruitment of leukocytes in the process of inflammation. CD40 ligation on ECs, smooth muscle cells, and macrophages initiates the expression and release of matrix-degrading enzymes, the MMPs. These enzymes, which degrade ECM proteins, significantly contribute to destruction and remodeling of inflamed tissue. Activated platelets release MMP-2 during aggregation (33, 44). Furthermore, adhesion of activated platelets to ECs results in generation and secretion of MMP-9 and of the protease receptor urokinase-type plasminogen activator receptor (uPAR) on cultured endothelium (45). The endothelial release of MMP-9 is dependent on both the fibrinogen receptor GPIIb/IIIa and CD40L, since inhibition of either mechanism resulted in reduction of platelet-induced matrix degradation activity of ECs. Moreover, GPIIb/IIIa ligation results in substantial release of CD40L in the absence of any further platelet agonist (45, 46) (Figure 2). These results suggest that the release of platelet-derived proinflammatory mediators like CD40L is dependent on GPIIb/IIIa–mediated adhesion. This mechanism may be pathophysiologically important to localize platelet-induced inflammation of the endothelium at a site of firm platelet-endothelium adhesion.
The L-type calcium channel in the heart: the beat goes on
Ilona Bodi, Gabor Mikala, Sheryl E. Koch, Shahab A. Akhter, and Arnold Schwartz
Sydney Ringer would be overwhelmed today by the implications of his simple experiment performed over 120 years ago showing that the heart would not beat in the absence of Ca2+. Fascination with the role of Ca2+ has proliferated into all aspects of our understanding of normal cardiac function and the progression of heart disease, including induction of cardiac hypertrophy, heart failure, and sudden death. This review examines the role of Ca2+ and the L-type voltage-dependent Ca2+ channels in cardiac disease.
When Sydney Ringer (1) discovered the vital role of Ca2+ in the heart, investigations took a leap forward and have continued unabated (2). Austrian scientist Otto Loewi, best known for his work on autonomic transmitters and discovery of "chemical vagusstoff," recognized the connection between digitalis and Ca2+ in 1917–1918. Although he always believed that Ca2+ was the key to understanding life’s processes, the Nobel Prize in Physiology and Medicine was awarded to Loewi and Sir Henry Hallett Dale in 1936 for their studies on neurotransmitters.
Ca2+ is the link in excitation-contraction (EC) coupling (Figure 1), which starts during the upstroke of the action potential (AP) and causes the opening of the L-type voltage-dependent Ca2+ channel (L-VDCC). Interest in high-voltage–activated L-VDCCs began with biochemical and continued with molecular characterizations, culminating in the cloning of the pore-forming 1 subunit and the auxiliary channel subunit 2/ from rabbit skeletal muscle (3-5). Although the L-VDCC subunits are most abundant in fast skeletal transverse tubules, Ca2+ influx is not required for contraction in skeletal muscle, unlike cardiac muscle, which requires Ca2+ entry with each beat and triggers Ca2+ release from the sarcoplasmic reticulum (SR) via Ca2+-release channels, e.g., ryanodine receptor 2 (RyR2). This amplifying process, termed Ca2+-induced Ca2+ release (CICR) by A. Fabiato, causes a rapid increase in intracellular Ca2+ concentration ([Ca2+]i) (from 100 nM to 1 µM) to a level required for optimal binding of Ca2+ to troponin C and induction of contraction (2). There is a close correlation between activation of the L-type Ca2+ current (ICa,L) and cardiac contraction. Contraction is followed by Ca2+ release from troponin C and its reuptake by the SR via activation of the SR Ca2+-ATPase 2a (SERCA2a) Ca2+ pump in addition to extrusion across the sarcolemma via the Na+/Ca2+ exchanger (NCX). In the human heart under resting conditions, the time required for cardiac myocyte depolarization, Ca2+-induced Ca2+ release, contraction, relaxation, and recovery is 600 ms. This process occurs approximately 70 times a minute or over 2 billion times in the average lifespan. Ca2+ is also required for maintenance of cell integrity and gene expression (6) relevant to the growth and development of the embryonic heart (7). L-VDCCs are regulated by the adrenergic nervous system and may interact with G protein–coupled receptors (8). 
Model for CDI and VDI. (A) Ca2+ channel at rest when no Ca2+ influx occurs. At rest, in the absence of Ca2+, the CaM binds to peptide A, located between the EF hand and the IQ motif of the C terminus of the L-VDCC 1C subunit. In response to a depolarizing stimulus, Ca2+ enters through the L-VDCC and binds to CaM. In the open Ca2+ channel state, the EF hand prevents structural conformation of the I–II loop required to block Ca2+ entry through the channel pore (B). In addition, the hydrophobic I1654 in the IQ motif is a stabilizing factor preventing the occlusion of the pore. Upon elevation of [Ca2+]i (depolarization), the Ca2+/CaM complex undergoes the Ca2+-dependent conformational change that relieves the inhibition of EF hand, permitting the I–II loop to interact with the pore and accelerate the fast inactivation process (C). The graph shows representative ICa traces evoked by depolarization from –50 mV to +40 mV, as labeled, using –60 mV as holding potential. (D) Involvement of CaM and CaMKII in the facilitation process. CaMKII enhances the ICa through phosphorylation of L-VDCC. We show murine whole-cell ICa generated from paired depolarizing pulses (–60 mV ± 10 mV at 0.5 Hz) representing Ca2+-dependent facilitation (graph).
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