These data suggest that the increased mortality during endotoxemia in HO-1(-/-) mice is related to increased oxidative stress and end-organ (renal and hepatic) damage, not to refractory hypotension.

Abstract-Heme oxygenase (HO) is a cytoprotective enzyme that degrades heme (a potent oxidant) to generate carbon monoxide (a vasodilatory gas that has anti-inflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO and its products, we hypothesized that HO would be important for the regulation of blood pressure and ischemic injury. We studied chronic renovascular hypertension in mice deficient in the inducible isoform of HO (HO-1) using a one kidney-one clip (1K1C) model of disease. Systolic blood pressure was not different between wild-type (HO-1 ϩ/ϩ ), heterozygous (HO-1 ϩ/Ϫ ), and homozygous null (HO-1 Ϫ/Ϫ ) mice at baseline. After 1K1C surgery, HO-1 ϩ/ϩ mice developed hypertension (140Ϯ2 mm Hg) and cardiac hypertrophy (cardiac weight index of 5.0Ϯ0.2 mg/g) compared with sham-operated HO-1 ϩ/ϩ mice (108Ϯ5 mm Hg and 4.1Ϯ0.1 mg/g, respectively). However, 1K1C produced more severe hypertension (164Ϯ2 mm Hg) and cardiac hypertrophy (6.9Ϯ0.6 mg/g) in HO-1 Ϫ/Ϫ mice. HO-1 Ϫ/Ϫ mice also experienced a high rate of death (56%) within 72 hours after 1K1C surgery compared with HO-1 ϩ/ϩ (25%) and HO-1 ϩ/Ϫ (28%) mice. Assessment of renal function showed a significantly higher plasma creatinine in HO-1 Ϫ/Ϫ mice compared with HO-1 ϩ/Ϫ mice. Histological analysis of kidneys from 1K1C HO-1 Ϫ/Ϫ mice revealed extensive ischemic injury at the corticomedullary junction, whereas kidneys from sham HO-1 Ϫ/Ϫ and 1K1C HO-1 ϩ/Ϫ mice appeared normal. Taken together, these data suggest that chronic deficiency of HO-1 does not alter basal blood pressure; however, in the 1K1C model an absence of HO-1 leads to more severe renovascular hypertension and cardiac hypertrophy. Moreover, renal artery clipping leads to an acute increase in ischemic damage and death in the absence of HO-1. (Circ Res. 2001;88:1088-1094.) Key Words: hypertension Ⅲ ischemia Ⅲ oxidative injury Ⅲ endothelin H eme oxygenase (HO) is the enzyme that catalyzes the initial reaction in heme catabolism. 1 The inducible isoform, HO-1, is upregulated by diverse stimuli including mediators of oxidative stress. 2,3 HO-1 is a cytoprotective enzyme 4 -6 that degrades heme (a potent oxidant) to generate carbon monoxide (CO, a vasodilatory gas that has antiinflammatory properties), bilirubin (an antioxidant derived from biliverdin), and iron (sequestered by ferritin). Because of properties of HO-1 and its products, it is believed that HO-1 may play an important role in cellular antioxidant defense mechanisms.Sacerdoti et al 7 and Escalante et al 8 have demonstrated that either acute or chronic administration of an inducer of HO-1 (stannous chloride) to spontaneously hypertensive rats led to a normalization of blood pressure. Other inducers of HO-1 or HO substrates have also been shown to decrease blood pressure in hypertensive rats. 9 -11 This response is not limited to the systemic vasculature, because inducers of HO-1 can prevent the development of hypoxic pulmonary hypertension. 12 In addition, it has...