Abstract:
:Gap junction pharmacology is a nascent field. Previous studies have identified molecules that enhance intercellular communication, and may offer potential for innovative antiarrhythmic therapy. However, their specific molecular target(s) and mechanism(s) of action remain unknown. Previously, we identified a 34-aa peptide (RXP-E) that binds the carboxyl terminal domain of Cx43 (Cx43CT) and prevents cardiac gap junction closure and action potential propagation block. These results supported the feasibility of a peptide-based pharmacology to Cx43, but the structure of the core active element in RXP-E, an essential step for pharmacological development, remained undefined. Here, we used a combination of molecular modeling, surface plasmon resonance, nuclear magnetic resonance and patch-clamp strategies to define, for the first time, a unique ensemble of pharmacophores that bind Cx43CT and prevent closure of Cx43 channels. Two particular molecules are best representatives of this family: a cyclized heptapeptide (called CyRP-71) and a linear octapeptide of sequence RRNYRRNY. These 2 small compounds offer the first structural platform for the design of Cx43-interacting gap junction openers. Moreover, the structure of these compounds offers an imprint of a region of Cx43CT that is fundamental to gap junction channel function.
journal_name
Circ Resjournal_title
Circulation researchauthors
Verma V,Larsen BD,Coombs W,Lin X,Spagnol G,Sorgen PL,Taffet SM,Delmar Mdoi
10.1161/CIRCRESAHA.109.200576subject
Has Abstractpub_date
2009-07-17 00:00:00pages
176-84issue
2eissn
0009-7330issn
1524-4571pii
CIRCRESAHA.109.200576journal_volume
105pub_type
杂志文章abstract:RATIONALE:Abdominal aortic aneurysms (AAAs) are characterized by pathological remodeling of the aortic wall. Although both increased Krüppel-like factor 5 (KLF5) expression and macrophage infiltration have been implicated in vascular remodeling, the role of KLF5 in macrophage infiltration and AAA formation remains uncl...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.116.310367
更新日期:2017-03-03 00:00:00
abstract:RATIONALE:Giant-cell arteritis (GCA) is a large-vessel vasculitis characterized by immune cell infiltration, yet the potential involvement of neutrophils has rarely been studied. OBJECTIVE:We investigated whether alterations in neutrophil reactivity occurred in the pathogenesis of GCA or during its clinical management...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.114.301374
更新日期:2014-01-17 00:00:00
abstract::We discuss the recent finding by Mizishima's group regarding the role of the autophagy-related conjugation system in mediating the closure of autophagosomes and its implication in the study of autophagy in mammalian cells. The study not only shows a novel function of the autophagy-related conjugation system but also i...
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pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.117.310450
更新日期:2017-02-17 00:00:00
abstract::Nonischemic dilated cardiomyopathy (DCM) often has a genetic pathogenesis. Because of the large number of genes and alleles attributed to DCM, comprehensive genetic testing encompasses ever-increasing gene panels. Genetic diagnosis can help predict prognosis, especially with regard to arrhythmia risk for certain subty...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.116.309396
更新日期:2017-09-15 00:00:00
abstract::The past 2 decades have witnessed a >40% improvement in mortality for patients with heart failure and left ventricular systolic dysfunction. 1 This success has coincided with the stepwise availability of drugs that target neurohormonal activation: β-adrenergic receptor blockers (β-blockers), ACE (angiotensin-convertin...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.118.313650
更新日期:2019-05-24 00:00:00
abstract::The impact of vanadate on the Na,K-ATPase system in the vascular smooth muscle cell is poorly understood. The present study describes the kinetics of the effect of vanadate on Na,K-ATPase and the Na-K pump in in vitro grown rat VSMC's. Vanadate interaction with the Na,K-ATPase system in vascular smooth muscle cells wa...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.53.2.186
更新日期:1983-08-01 00:00:00
abstract:RATIONALE:We studied a possibility that shRNAs can lead to transcriptional gene activation at the promoter level via epigenetic mechanism. OBJECTIVE:The purpose of this study was to test the effects on vascular endothelial growth factor (VEGF-A) expression by promoter targeted small hairpin RNAs (shRNAs) in vitro and ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.109.200774
更新日期:2009-09-11 00:00:00
abstract::Glycerophosphate and carnitine as competing acyl acceptors and the oxidation of different long chain acylcarnitines in isolated mitochondria have been investigated. In the presence of low concentrations of palmitate, glycerophosphate is the preferred acyl acceptor in isolated liver mitochondria, indicating that the gl...
journal_title:Circulation research
pub_type: 杂志文章
doi:
更新日期:1976-05-01 00:00:00
abstract::Myocardial stunning is a form of reversible myocardial ischemia/reperfusion injury associated with systolic and diastolic contractile dysfunction. In the isolated rat heart model, myocardial stunning is characterized by specific C-terminal proteolysis of the myofilament protein, troponin I (cTnI) that yields cTnI1-193...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000099889.35340.6F
更新日期:2003-11-14 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.107.150417
更新日期:2007-08-17 00:00:00
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journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.63.6.1020
更新日期:1988-12-01 00:00:00
abstract::Although Ca(2+) waves in cardiac myocytes are regarded as arrhythmogenic substrates, their properties in the heart in situ are poorly understood. On the hypothesis that Ca(2+) waves in the heart behave diversely and some of them influence the cardiac function, we analyzed their incidence, propagation velocity, and int...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.86.10.1093
更新日期:2000-05-26 00:00:00
abstract::-ATP-sensitive potassium (K(ATP)) channels were discovered in ventricular cells, but their roles in the heart remain mysterious. K(ATP) channels have also been found in numerous other tissues, including vascular smooth muscle. Two pore-forming subunits, Kir6.1 and Kir6.2, contribute to the diversity of K(ATP) channels...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.88.6.570
更新日期:2001-03-30 00:00:00
abstract::It is well known that electrical pacing may either terminate or change the rate and/or ECG appearance of reentrant ventricular tachycardia. However, the dynamics of interaction of reentrant waves with waves initiated by external pacing are poorly understood. Prevailing concepts are based on simplistic models in which ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.77.6.1166
更新日期:1995-12-01 00:00:00
abstract::As described in earlier reviews in this series on the molecular basis of hypertrophic cardiomyopathy (HCM), HCM is one of the archetypal monogenic cardiovascular disorders to be understood at the molecular level. Twenty years after the discovery of the first HCM disease gene, genetic studies still confirm that HCM is ...
journal_title:Circulation research
pub_type: 杂志文章,评审
doi:10.1161/CIRCRESAHA.111.242974
更新日期:2011-06-24 00:00:00
abstract::Heparin inhibits the development of intimal thickening after carotid injury in the rat; however, the specific cellular events responsible for this effect have not been defined. In this study, smooth muscle cell growth fraction and migration into the intima were quantitatively measured in heparin-treated animals. All r...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.58.6.839
更新日期:1986-06-01 00:00:00
abstract::Effects of blood flow on the production of prostacyclin (PGI2) were examined in the canine femoral artery perfused ex vivo. Each artery was perfused in situ with medium 199, under conditions of simulated blood flow. To simulate the normal and abnormal blood flow waveforms at the same mean flow rate, we developed a flo...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.68.4.1095
更新日期:1991-04-01 00:00:00
abstract::Oxidative stress has been suggested to potentiate atherogenesis. However, studies that have investigated the effect of antioxidants on atherosclerosis showed inconsistent results, ie, atherosclerosis was either retarded or not changed by dietary antioxidants. This report directly examined the effect of overexpressing ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.RES.0000149564.49410.0d
更新日期:2004-11-26 00:00:00
abstract::We studied product inhibition of the actin-activated ATPase of myosin subfragment-1 (S-1) from the three types of muscle tissue: skeletal, cardiac, and smooth. Increasing levels of [MgADP] in the 0-1-mM range caused significant inhibition of the actin-activated MgATPase activity of cardiac and gizzard but not skeletal...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.71.5.1067
更新日期:1992-11-01 00:00:00
abstract::Although urinary sodium excretion is positively influenced by acute changes in renal perfusion pressure, micropuncture studies show highly conflicting results concerning the response of superficial proximal tubule sodium reabsorption to changes in renal perfusion pressure. In the present study, the changes of superfic...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.66.5.1184
更新日期:1990-05-01 00:00:00
abstract::We recorded 60 DC simultaneous electrograms from isolated porcine and canine hearts in the first minutes after coronary occlusion. Ventricular premature beats (VPB) originated from the normal side of the ischemic border, which was frequently separated from the central ischemic area showing delayed activity by a small ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.50.4.527
更新日期:1982-04-01 00:00:00
abstract::Large-conductance Ca2+-dependent K+ channels (KCa), which are abundant on the sarcolemma of vascular myocytes, provide negative feedback via membrane hyperpolarization that limits Ca2+ entry through L-type Ca2+ channels (ICaL). We hypothesize that local accumulation of subsarcolemmal Ca2+ during ICaL openings amplifie...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.84.9.1032
更新日期:1999-05-14 00:00:00
abstract:RATIONALE:Transcatheter, intramyocardial injections of bone marrow-derived cell therapy produces reverse remodeling in large animal models of ischemic cardiomyopathy. OBJECTIVE:We used cardiac MRI (CMR) in patients with left ventricular (LV) dysfunction related to remote myocardial infarction (MI) to test the hypothes...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.111.242610
更新日期:2011-04-01 00:00:00
abstract:RATIONALE:Remodeling of the vessel wall and the formation of vascular networks are dynamic processes that occur during mammalian embryonic development and in adulthood. Plaque development and excessive neointima formation are hallmarks of atherosclerosis and vascular injury. As our understanding of these complex proces...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/CIRCRESAHA.119.315804
更新日期:2020-02-28 00:00:00
abstract::We performed morphological studies of myocardial contracture to define its nature and relationship to mechanical changes occurring during metabolic blockade. Isolated rat papillary and trabecular muscles were stretched to the apices of their length-tension curves and stimulated to contract isometrically 12 times a min...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.45.2.298
更新日期:1979-08-01 00:00:00
abstract::The direct-current magnetocardiogram, which shows the T-Q (baseline) shift, is used to clarify the cause of S-T depression induced by stress testing in the human heart. Measurements are made of the amount of baseline shift associated with the S-T depression. Results are presented of a well-documented patient, with typ...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.53.2.274
更新日期:1983-08-01 00:00:00
abstract::Catecholamines have been implicated in the phenomenon of ischemic preconditioning. We have previously demonstrated that ischemic preconditioning against postischemic mechanical dysfunction in the isolated rat heart is mediated by the alpha 1-adrenergic receptor. The purpose of this study was to delineate the signal tr...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.76.1.73
更新日期:1995-01-01 00:00:00
abstract::The present study was designed to test the ability of regenerated endothelium to evoke endothelium-dependent hyperpolarizations. Hyperpolarizations induced by serotonin and bradykinin were compared in isolated porcine coronary arteries with native or regenerated endothelium, 4 weeks after balloon endothelial denudatio...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.84.4.371
更新日期:1999-03-05 00:00:00
abstract::The signaling pathways involved in the long-term metabolic effects of angiotensin II (Ang II) in vascular smooth muscle cells are incompletely understood but include the generation of molecules likely to affect oxidase activity. We examined the ability of Ang II to stimulate superoxide anion formation and investigated...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.74.6.1141
更新日期:1994-06-01 00:00:00
abstract::The circulatory effects associated with lifelong plasma atrial natriuretic factor (ANF) elevation were examined by generating transgenic mice, which constitutively express a fusion gene consisting of the transthyretin promoter and the ANF structural gene. These mice have chronically elevated ANF levels as compared wit...
journal_title:Circulation research
pub_type: 杂志文章
doi:10.1161/01.res.74.4.747
更新日期:1994-04-01 00:00:00