Induction of heme oxygenase produces load-independent cardioprotective effects in hypertensive rats

Seki, Toshiro; Naruse, Mitsuhide; Naruse, Kiyoko; Yoshimoto, Takanobu; Tanabe, Akiyo; Seki, Momoko; Tago, Katsuya; Imaki, Toshihiro; Demura, Reiko; Demura, Hiroshi

doi:10.1016/s0024-3205(99)00338-0

Cited by 30 publications

(15 citation statements)

References 25 publications

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“…Interestingly, HO-1 knockout mice exposed to hypoxia exhibit significantly greater ventricular hypertrophy compared to wild type controls, suggesting that the induction of HO-1 may function in an autocrine manner to limit cardiac hypertrophy (Yet et al, 1999). In support of this proposal, the induction of HO-1 by stannous chloride attenuates left ventricular/ body weight ratio in genetically hypertensive rats (Seki et al, 1999). These findings also demonstrate that HO-1 attenuates both load-dependent and -independent forms of cardiac hypertrophy.…”

Section: Ho-1 and Cell Hypertrophymentioning

confidence: 89%

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Durante

2003

Journal Cellular Physiology

143

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Heme oxygenase-1 (HO-1) catalyzes the degradation of heme to carbon monoxide (CO), iron, and biliverdin. Biliverdin is subsequently metabolized to bilirubin by the enzyme biliverdin reductase. Although interest in HO-1 originally centered on its heme-degrading function, recent findings indicate that HO-1 exerts other biologically important actions. Emerging evidence suggests that HO-1 plays a critical role in growth regulation. Deletion of the HO-1 gene or inhibition of HO-1 activity results in growth retardation and impaired fetal development, whereas HO-1 overexpression increases body size. Although the mechanisms responsible for the growth promoting properties of HO-1 are not well established, HO-1 can indirectly influence growth by regulating the synthesis of growth factors and by modulating the delivery of oxygen or nutrients to specific target tissues. In addition, HO-1 exerts important effects on critical determinants of tissue size, including cell proliferation, apoptosis, and hypertrophy. However, the actions of HO-1 are highly variable and may reflect a role for HO-1 in maintaining tissue homeostasis. Considerable evidence supports a crucial role for HO-1 in blocking the growth of vascular smooth muscle cells (SMCs). This antiproliferative effect of HO-1 is mediated primarily via the release of CO, which inhibits vascular SMC growth via multiple pathways. Pharmacologic or genetic approaches targeting HO-1 or CO to the blood vessel wall may represent a promising, novel therapeutic approach in treating vascular proliferative disorders.

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Section: Ho-1 and Cell Hypertrophymentioning

confidence: 89%

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Durante

2003

Journal Cellular Physiology

143

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“…In accordance with this, a previous study has also demonstrated that HO-1 induction attenuates cardiac hypertrophy in stroke-prone SHR rats via a pressureindependent mechanism. 28 Circumstantial evidence has supported the roles of bilirubin and CO, the byproducts of heme degradation, in the cytoprotective functions of HO-1 in vitro and in vivo. 5 Our data show that bilirubin exhibits suppressive effect on Ang II-induced hypertrophic response through the reduction of ROS production, which is implicated in the growth response signaling in cardiomyocytes.…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Inhibits Angiotensin II-Induced Cardiac Hypertrophy In Vitro and In Vivo

et al. 2004

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“…This response paralleled the hypertensive response shown in Figure 1. However, Seki et al 39 have shown in spontaneously hypertensive rats that chronic administration of an inducer of HO-1 (stannous chloride), at a dose that does not alter systemic blood pressure, can attenuate the development of cardiac hypertrophy. This may suggest that beyond a regulation of systemic blood pressure, HO-1 may have independent effects on the development of cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

Exacerbation of Chronic Renovascular Hypertension and Acute Renal Failure in Heme Oxygenase-1–Deficient Mice

Wiesel

Patel²,

Carvajal³

et al. 2001

Circulation Research

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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...

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Induction of heme oxygenase produces load-independent cardioprotective effects in hypertensive rats

Cited by 30 publications

References 25 publications

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Heme oxygenase‐1 in growth control and its clinical application to vascular disease

Heme Oxygenase-1 Inhibits Angiotensin II-Induced Cardiac Hypertrophy In Vitro and In Vivo

Exacerbation of Chronic Renovascular Hypertension and Acute Renal Failure in Heme Oxygenase-1–Deficient Mice

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