P203
Heme oxygenase (HO) catalyzes the conversion of heme to biliverdin, free iron and carbon monoxide (CO). Both heme and CO have been implicated in the regulation of vascular tone. We report the successful cloning of the human HO-1 cDNA (HHO-1) into a LXSN retroviral vector (LSN-HHO-1). A single intra-left ventricular delivery of 1×10
10
pfu/ml of LSN-HHO-1 to 5-day-old spontaneously hypertensive rats (SHR; n = 32) resulted in extended expression of the human HO-1 (mRNA and protein) in several tissues, including the kidney, liver, spleen, lung, heart, brain and aorta. The expression of HHO-1 was associated with a 2-3 fold increase in HO activity in these tissues. Mean blood pressure (MBP) of SHR injected with LSN-HHO-1 was significantly
lower than that of SHR injected with the control empty vector LXSN, by 4 weeks of age (144±4.6 mmHg vs 164.8±6.5 mmHg,
n=32, *
p
<0.01). SHR treated with LSN-HHO-1 demonstrated a consistent reduction in MBP of ≈20 ± 4 mmHg when compared with the control LXSN injected SHR throughout the 20 weeks of the experiment. Administration of
the HO inhibitor, stannic mesoporphyrin (Sn MP), to LSN-HHO-1-treated SHR resulted in a 15 to 18 mmHg rise of MBP, further suggesting that increased HO expression underlie, at least in part, the blood pressure lowering effect of LSN-HHO-1. Rats expressing HHO-1 showed significant reduction in the urinary excretion of the vasoconstrictor cytochrome P-450 arachidonate metabolite, 20-HETE. Moreover, gracilis muscle arterioles (≈ 55μm in diameter) isolated from HHO-1 transgenic SHR showed less contractile responses to increased intraluminal pressure than vessels isolated from LXSN-treated SHR; this effect was reversed by the addition of SnMP. Interestingly, HHO-1 transgenic rats showed significant proportionate increase in somatic growth, i.e., nose to tail length, fibula length and body weight gain. These studies demonstrate
that delivery of the human HO-1 gene by a retroviral vector results in permanent expression
of HHO-1, long-term reduction in blood pressure together with growth promoting activity in the
SHR.
Human Heme Oxygenase-1 Gene Transfer Lowers Blood Pressure and Promotes Growth in Spontaneously Hypertensive Rats