Hybrid Structural Analysis of the Arp2/3 Regulator Arpin Identifies Its Acidic Tail as a Primary Binding Epitope

Arpin is a newly discovered regulator of actin polymerization at the cell leading edge, which steers cell migration by exerting a negative control on the Arp2/3 complex. Arpin proteins have an acidic tail homologous to the acidic motif of the VCA domain of nucleation-promoting factors (NPFs). This tail is predicted to compete with the VCA of NPFs for binding to the Arp2/3 complex, thereby mitigating activation and/or tethering of the complex to sites of actin branching. Here, we investigated the structure of full-length Arpin using synchrotron small-angle X-ray scattering, and of its acidic tail in complex with an ankyrin repeats domain using X-ray crystallography. The data were combined in a hybrid model in which the acidic tail extends from the globular core as a linear peptide and forms a primary epitope that is readily accessible in unbound Arpin and suffices to tether Arpin to interacting proteins with high affinity

Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy

AbstractOBJECTIVESThis study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors attenuate beta-adrenergic contractility in patients with idiopathic dilated cardiomyopathy (DCM) through nitric oxide (NO) myocardial signaling.BACKGROUNDThe ACE inhibitors increase bradykinin, an agonist of NO synthase (NOS). Nitric oxide inhibits beta-adrenergic myocardial contractility in patients with heart failure.METHODSThe study patients were given the angiotensin-1 (AT-1) receptor antagonist losartan for one week. The hemodynamic responses to intravenous dobutamine were determined before and during intracoronary infusion of enalaprilat (0.2 mg/min) with and without the NOS inhibitor NG-monomethyl-L-arginine (L-NMMA, 5 mg/min).RESULTSIn patients with DCM (n = 8), dobutamine increased the peak rate of rise of left ventricular pressure (+dP/dt) by 49 ± 8% (p < 0.001) and ventricular elastance (Ees) by 53 ± 16% (p < 0.03). Co-infusion with enalaprilat decreased +dP/dt to 26 ± 12% and Eesto −2 ± 17% above baseline (p < 0.05), and this anti-adrenergic effect was reversed by L-NMMA co-infusion (p < 0.05 vs. enalaprilat). In addition, intracoronary enalaprilat reduced left ventricular end-diastolic pressure (LVEDP), but not left ventricular end-diastolic volume, consistent with increased left ventricular distensibility. Infusion with L-NMMA before enalaprilat in patients with DCM (n = 5) prevented the reduction in +dP/dt, Eesand LVEDP. In patients with normal left ventricular function (n = 5), enalaprilat did not inhibit contractility or reduce LVEDP during dobutamine infusion.CONCLUSIONSEnalaprilat attenuates beta-adrenergic contractility and enhances left ventricular distensibility in patients with DCM, but not in subjects with normal left ventricular function. This response is NO modulated and occurs in the presence of angiotensin receptor blockade. These findings may have important clinical and pharmacologic implications for the use of ACE inhibitors, AT-1 receptor antagonists and their combination in the treatment of heart failure

A Simple Adaptive Transfer Function for Deriving the Central Blood Pressure Waveform from a Radial Blood Pressure Waveform

Publisher's PDFGeneralized transfer functions (GTFs) are available to compute the more relevant central blood pressure (BP) waveform from a more easily measured radial BP waveform. However, GTFs are population averages and therefore may not adapt to variations in pulse pressure (PP) amplification (ratio of radial to central PP). A simple adaptive transfer function (ATF) was Developmenteloped. First, the transfer function is defined in terms of the wave travel time and reflection coefficient parameters of an arterial model. Then, the parameters are estimated from the radial BP waveform by exploiting the observation that central BP waveforms exhibit exponential diastolic decays. The ATF was assessed using the original data that helped popularize the GTF. These data included radial BP waveforms and invasive reference central BP waveforms from cardiac catheterization patients. The data were divided into low, middle, and high PP amplification groups. The ATF estimated central BP with greater accuracy than GTFs in the low PP amplification group (e.g., central systolic BP and PP root-mean-square-errors of 3.3 and 4.2 mm Hg versus 6.2 and 7.1 mm Hg; p <= 0.05) while showing similar accuracy in the higher PP amplification groups. The ATF may permit more accurate, non-invasive central BP monitoring in elderly and hypertensive patients.University of Delaware, Department of Kinesiology & Applied Physiolog