The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release-inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses. These findings from studies on humans suggest a mechanism whereby diminished catestatin might increase the risk for hypertension. We generated Chga -/-and humanized mice through transgenic insertion of a human CHGA haplotype in order to probe CHGA and catestatin in vivo.

Heart failure is accompanied by severely impaired ␤-adrenergic receptor (␤AR) function, which includes loss of ␤AR density and functional uncoupling of remaining receptors. An important mechanism for the rapid desensitization of ␤AR function is agonist-stimulated receptor phosphorylation by the ␤AR kinase (␤ARK1), an enzyme known to be elevated in failing human heart tissue. To investigate whether alterations in ␤AR function contribute to the development of myocardial failure, transgenic mice with cardiac-restricted overexpression of either a peptide inhibitor of ␤ARK1 or the ␤ 2 AR 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 ؊͞؊ ͞␤ 2 AR mice had enlarged left ventricular (LV) chambers with significantly reduced fractional shortening and mean velocity of circumferential fiber shortening. In contrast, MLP ؊͞؊ ͞␤ARKct mice had normal LV chamber size and function. Basal LV contractility in the MLP ؊͞؊ ͞␤ARKct mice, as measured by LV dP͞dtmax, was increased significantly compared with the MLP ؊͞؊ mice but less than controls. Importantly, heightened ␤AR 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 ␤ARK1 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 ␤AR-G protein coupling in the pathogenesis of the failing heart and point the way toward development of agents to inhibit ␤ARK1 as a novel mode of therapy.One of the most important mechanisms for rapidly regulating ␤-adrenergic receptor (␤AR) function is agonist-stimulated receptor phosphorylation by G protein-coupled receptor kinases (GRKs) resulting in decreased sensitivity to further catecholamine stimulation (1, 2). ␤ARK1 is a member of the multigene GRK family that regulates a wide variety of receptors that couple to heterotrimeric G proteins (1, 2). Desensitization of agonistoccupied receptors by the cytosolic ␤AR kinase (␤ARK1) requires a membrane-targeting event before its activation and receptor phosphorylation, which is mediated by a direct physical interaction between residues within the carboxyl terminus of ␤ARK1 and the dissociated membrane-anchored ␤␥ subunits of G proteins (G␤␥) (3, 4).Heart failure is a disease characterized by left ventricular (LV) dysfunction associated with a complex of symptoms that relate to inadequate perfusion of tissues and pulmonary congestion. Although the fundamental molecular abnormality that causes this progressive deterioration in cardiac function is unknown, one of the leading candidates is abnormal ␤AR signaling. Chronic human heart failure is characterized by severely attenuated ␤AR signaling, resulting from diminished receptor number and impaired receptor function (5...

The role of the cardiac myocyte as a mediator of paracrine signaling in the heart has remained unclear. To address this issue, we generated mice with cardiac myocyte-specific deletion of the vascular endothelial growth factor gene, thereby producing a cardiomyocyte-specific knockout of a secreted factor. The hearts of these mice had fewer coronary microvessels, thinned ventricular walls, depressed basal contractile function, induction of hypoxiaresponsive genes involved in energy metabolism, and an abnormal response to ␤-adrenergic stimulation. These findings establish the critical importance of cardiac myocyte-derived vascular endothelial growth factor in cardiac morphogenesis and determination of heart function. Further, they establish an adult murine model of hypovascular nonnecrotic cardiac contractile dysfunction.

Anesthetics provide sedation and immobility facilitating echocardiography in mice, but influence cardiac function. We studied the effects of intraperitoneal and inhaled anesthetic agents on echocardiographic measurements. Mice were anesthetized with intraperitoneal tribromoethanol (TBE), ketamine-midazolam (K/M), ketamine-xylazine (K/X), or inhaled isoflurane (Isf), and echocardiographic parameters were assessed at 5, 10, 15, and 20 min. In C57BL/6N mice, Isf produced high initial heart rates (HR) that decreased to levels comparable to TBE at 15-20 min (approximately 450 beats/min) and the most stable percent fractional shortening (%FS) and end-diastolic dimension (EDD). With TBE, %FS initially was low, but increased comparable to Isf (approximately 45%) at 15 min. K/M produced similar time trends but lower absolute values compared with TBE for all parameters. K/X produced cardiac depression evidenced by low HR and %FS, and increased EDD. Isf was the most reproducible in repeat studies at 12 days. In C57BL/6J compared with C57BL/6N mice, K/M produced higher HR, and %FS and TBE produced smaller EDD. In conclusion, anesthetic agent, timing of echocardiographic measurements, and genetic background are all critical variables during echocardiography in mice.