Homologous recombination guided ablation of the chromogranin a gene: Hemodynamic changes and rescue of the elevated blood pressure by the human ortholog

Chromogranin A (CHGA), a 48 kDa secretory pro-hormone, is the major protein co-stored and co-released with catecholamines from secretory vesicles in adrenal medulla and postganglionic sympathetic axons. CHGA is over-expressed in essential hypertension, a complex trait with genetic predisposition. Conversely, the plasma concentration of the catestatin fragment of CHGA is diminished both in established hypertension and in patients’ still-normotensive offspring at genetic risk of developing the disease. These human findings suggest a mechanism whereby diminished catestatin might increase the risk for hypertension. We generated Chga null (Chga-/-) and “humanized” CHGA mice to probe CHGA and catestatin in vivo. Telemetric and tail-cuff studies on blood pressure (BP), transthoracic echocardiography, and hemodynamic studies reveal extreme cardiovascular changes in Chga-/mice: (i) Elevated systolic and diastolic BP (by up to 43.7 mmHg); (ii) Loss of diurnal BP variation; (iv) Increased left ventricular mass (by 72%) and cavity dimensions (by 18–47%); (iii) higher heart rate, left ventricular pressure, ventricular contractility (max dP/dt) and end diastolic pressure and lower R-R intervals (iv) Increased plasma catecholamines and Npy (by 162–214%). Rescue of elevated BP to normalcy was achieved by either exogenous catestatin replacement, or “humanization” of Chga-/mice with transgenic insertion of a human CHGA haplotype. For the first time it is apparent that the human gene has a definitive role in autonomic control of the circulation. The “humanized” transgenic mice provide a model system for functional analyses of the human CHGA gene. Loss of the physiological “brake” catestatin in Chga-/mice, coupled with dysregulation of transmitter storage and release, may act in concert to alter autonomic control of the circulation in vivo, eventuating in hypertension.