Genetically-Programmed Suicide of Adrenergic Cells in Mice Produces Left Ventricular Dysfunction as Revealed by High-Resolution Echocardiography

The enzyme Phenylethanolamine-N-methyltransferase (Pnmt), which catalyzes the conversion of norepinephrine into epinephrine, serves as a marker for adrenergic cells and is expressed in the developing heart. In the present study, we tested the hypothesis that adrenergic cells play an important role in the development of cardiac function by assessing phenotypes of mice with selective ablation of adrenergic cells compared with littermate controls. Briefly, Pnmt-Cre knock-in mice were crossed with ROSA26-eGFP-DTA mice, which results in selective ablation of Pnmt+ adrenergic cells due to activation of the Diphtheria Toxin Alpha (DTA) “suicide” allele from the ROSA26 locus. Control experiments verified that the model was working correctly since Pnmt-Cre/DTA mice had markedly lower Pnmt mRNA (>97% decrease) and fewer Pnmt+ cells (>50% decrease) in adrenal glands compared to littermate controls. Pnmt-Cre/DTA mice were born in normal Mendelian ratios and appeared outwardly normal and healthy at birth and during the early postnatal period, but began to show cardiac deficits by one month of age. High-resolution echocardiography analysis indicated continuing deterioration of cardiac function with age. Mean cardiac output was decreased at four months (10.81±2.73 mL/min n=14 v 18.42±3.37 mL/min n=18, p-value<0.001, Fig. 1), as was ejection fraction (54.34±7.44% v 66.53±8.51%, p<0.01), and fractional shortening (27.64±4.80% v 36.67±7.22%, p<0.01). Moreover, left ventricular function was hypokinetic in the ablated hearts compared to controls, as shown in the M-mode tracings in Fig. 1. These data demonstrate that selective ablation of adrenergic cells leads to impaired cardiac function that progressively worsens with age over the first few months after birth. In conclusion, this novel cellular suicide model is useful for determining how adrenergic cells contribute to the development of cardiac structure and function. ![][1] [1]: /embed/graphic-1.gif