Expression of a β-adrenergic receptor kinase 1 inhibitor prevents the development of myocardial failure in gene-targeted mice

Heart failure is accompanied by severely impaired β-adrenergic receptor (βAR) function, which includes loss of βAR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of βAR function is agonist-stimulated receptor phosphorylation by the βAR kinase (βARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in βAR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of βARK1 or the β2AR were mated into a genetic model of murine heart failure (MLP−/−). In vivo cardiac function was assessed by echocardiography and cardiac catheterization. Both MLP−/− and MLP−/−/β2AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP−/−/βARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP−/−/βARKct mice, as measured by LV dP/dtmax, was increased significantly compared with the MLP−/− mice but less than controls. Importantly, heightened βAR desensitization in the MLP−/− mice, measured in vivo (responsiveness to isoproterenol) and in vitro (isoproterenol-stimulated membrane adenylyl cyclase activity), was completely reversed with overexpression of the βARK1 inhibitor. We report here the striking finding that overexpression of this inhibitor prevents the development of cardiomyopathy in this murine model of heart failure. These findings implicate abnormal βAR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit βARK1 as a novel mode of therapy.

The first extrasolar planet discovered with a new-generation high-throughput Doppler instrument

We report the detection of the first extrasolar planet, ET-1 (HD 102195b), using the Exoplanet Tracker (ET), a new-generation Doppler instrument. The planet orbits HD 102195, a young star with solar metallicity that may be part of the local association. The planet imparts radial velocity variability to the star with a semiamplitude of 63.4 ± 2.0 m s^-1 and a period of 4.11 days. The planetary minimum mass (m sin i) is 0.488MJ ± 0.015M_J. The planet was initially detected in the spring of 2005 with the Kitt Peak National Observatory (KPNO) 0.9 m coudé feed telescope. The detection was confirmed by radial velocity observations with the ET at the KPNO 2.1 m telescope and also at the 9 m Hobby-Eberly Telescope (HET) with its High Resolution Spectrograph. This planetary discovery with a 0.9 m telescope around a V = 8.05 magnitude star was made possible by the high throughput of the instrument: 49% measured from the fiber output to the detector. The ET's interferometer-based approach is an effective method for planet detection. In addition, the ET concept is adaptable to multiple-object Doppler observations or very high precision observations with a cross-dispersed echelle spectrograph to separate stellar fringes over a broad wavelength band. In addition to spectroscopic observations of HD 102195, we obtained brightness measurements with one of the automated photometric telescopes at Fairborn Observatory. Those observations reveal that HD 102195 is a spotted variable star with an amplitude of ~0.015 mag and a 12.3 ± 0.3 day period. This is consistent with spectroscopically observed Ca II H and K emission levels and line-broadening measurements but inconsistent with rotational modulation of surface activity as the cause of the radial velocity variability. Our photometric observations rule out transits of the planetary companion.