Hif-1α is not required for the development of cardiac adrenergic control in zebrafish (Danio rerio)

Adrenergic regulation, acting via the sympathetic nervous system, provides a major mechanism to control cardiac function. It has recently been shown that hypoxia inducible factor-1α (Hif-1α) is necessary for normal development of sympathetic innervation and control of cardiac function in the mouse. To investigate whether this may represent a fundamental trait shared across vertebrates, we assessed adrenergic regulation of the heart in wild-type and Hif-1α knockout (hif-1α ^-/- ) zebrafish (Danio rerio). Wild-type and hif-1α ^-/- zebrafish larvae (aged 4 and 7 days postfertilisation) exhibited similar routine heart rates within a given age group, and β-adrenergic receptor blockade with propranolol universally reduced heart rate to comparable levels, indicating similar adrenergic tone in both genotypes. In adult fish, in vivo heart rate measured during anaesthesia was identical between genotypes. Treatment of spontaneously beating hearts in vitro with adrenaline revealed a similar positive chronotropic effect and similar maximum heart rates in both genotypes. Tyrosine hydroxylase immunohistochemistry with confocal microscopy demonstrated that the bulbus arteriosus (outflow tract of the teleost heart) of adult fish was particularly well innervated by sympathetic nerves, and nerve density (as a percentage of bulbus arteriosus area) was similar between wild-types and hif-1α ^-/- mutants. In summary, we did not find any evidence that adrenergic cardiac control was perturbed in larval or adult zebrafish lacking Hif-1α. We conclude that Hif-1α is not essential for the normal development of cardiovascular control or adult sympathetic cardiac innervation in zebrafish, although it is possible that it plays a redundant or auxiliary role.