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HEME OXYGENASE

Role of Heme Oxygenase-1 in the Regulation of Blood Pressure and Cardiac Function

Yen-Hsu Chen^*,, Shaw-Fang Yet^*, and Mark A. Perrella^*,,1

^* Pulmonary and Critical Care Division, Brigham and Women’s Hospital, Boston, Massachusetts 02115;
Harvard Medical School, Boston, Massachusetts 02115; and
Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, 807

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 the properties of inducible HO (HO-1) and its products, we hypothesized that HO-1 would play an important role in the regulation of cardiovascular function. In this article, we will review the role of HO-1 in the regulation of blood pressure and cardiac function and highlight previous studies from our laboratory using gene deletion and gene overexpression transgenic approaches in mice. These studies will include the investigation of HO-1 in the setting of hypertension (renovascular), hypotension (endotoxemia), and ischemia/reperfusion injury (heart). In a chronic renovascular hypertension model, hypertension, cardiac hypertrophy, acute renal failure, and acute mortality induced by one kidney–one clip surgery were more severe in HO-1-null mice. In addition, HO-1-null mice with endotoxemia had earlier resolution of hypotension, yet the mortality and the incidence of end-organ damage were higher in the absence of HO-1. In contrast, mice with cardiac-specific overexpression of HO-1 had an improvement in cardiac function, smaller myocardial infarctions, and reduced inflammatory and oxidative damage after coronary artery ligation and reperfusion. Taken together, these studies suggest that an absence of HO-1 has detrimental consequences, whereas overexpression of HO-1 plays a protective role in hypoperfusion and ischemia/reperfusion injury.

Key Words: blood pressure • cardiovascular • oxidative stress

Heme oxygenase (HO) is the first and rate-limiting enzyme in the heme breakdown to generate equimolar quantities of biliverdin, free ferrous iron, and carbon monoxide (CO). Subsequently, biliverdin is rapidly converted to bilirubin by biliverdin reductase, and free iron is sequestered by ferritin. Among the three reported HO isoforms (HO-1, -2, -3), HO-1 is ubiquitously expressed, particularly after induction by numerous stimuli, including heme and other oxidants, heavy metals, ultraviolet light, endotoxin, inflammation, proinflammatory cytokines, hypoxia, hyperoxia, and shear stress. HO-2 is constitutively expressed in many organs throughout the body, although particularly high in the brain and testes. HO-3, more recently identified, is similar to HO-2 in amino acid structure, but serves as a less efficient heme catalyst. For a more detailed overview of the HO system and the products of heme catabolism, please refer to previously published articles and reviews (1–9). The references sited are not exhaustive, but we attempted to provide references that contributed to concepts covered in this article.

HO-1 and the subsequent metabolites of heme catabolism appear to play vital roles in regulating important biological responses, including inflammation, oxidative stress, cell survival, and cell proliferation (10). The proposed mechanisms by which HO-1 exerts its biological effects include its ability to degrade the pro-oxidative heme, the release of biliverdin and subsequent conversion to bilirubin, both of which have antioxidant properties (11), and the generation of CO, which has vasodilatory, antiproliferative, and anti-inflammatory properties (10). In this article, we highlight the relationship of HO-1 and multiple organ damage resulting from oxidative injury, especially in the cardiovascular system, using HO-1 gene-targeting approaches in animal models of disease.

HO-1 and Blood Pressure Regulation

Hypertension.
Because of the properties of inducible HO (HO-1) and its products of heme catabolism (particularly CO), it is very reasonable to hypothesize that HO-1 would play an important role in the regulation of blood pressure. Sacerdoti et al. and Escalante et al. have demonstrated previously that either acute (12) or chronic (13) 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 (14–16). This response is not limited to the systemic vasculature because inducers of HO-1 can prevent the development of hypoxic pulmonary hypertension (17).

In addition to the response of inducing HO-1, investigators have also shown that treatment of normal rats with inhibitors of HO (metalloporphyrins) produce an increase in systemic arterial pressure (18). Although the effect of biliverdin on the prohypertensive effects of oxidative stress cannot be entirely excluded, the administration of biliverdin did not significantly alter blood pressure in these animals (18). Thus, these studies provided evidence that CO via the HO system may contribute to the regulation of systemic blood pressure. This concept regarding the cardiovascular effects of CO was first put forth in 1978 when it was demonstrated that CO could cause vasodilation in the pulmonary vasculature under normoxic condition and that CO could also reduce the pulmonary vascular vasoconstriction induced by hypoxia (19). Subsequent studies also showed a vasodilatory response of CO in other vascular beds, such as the coronary circulation (20). It appears that CO is able to regulate this vascular response by activating soluble guanylate cyclase and producing cGMP (4, 21, 22), which has vasodilatory properties. However, it has also been shown that CO may promote a vasodilatory response in vascular smooth muscle cells independent of cGMP by stimulating calcium-activated potassium channels (23, 24).

Beyond the direct vasodilatory effects of CO, Morita et al. have shown that vascular smooth muscle cell-derived CO inhibits production of the potent vasoconstrictor endothelin (ET)-1 (25). This inhibition may contribute to the effects of CO on vascular tone and blood pressure. Investigators have also demonstrated that angiotensin II-induced hypertension promotes induction of HO-1 (26–28), suggesting that upregulation of endogenous HO-1 may attempt to counteract the hypertensive effect of angiotensin II (Ang II).

Because many of the inducers or inhibitors of HO-1 are nonselective in their function, the specific overexpression of HO-1 by gene transfer (29) and the generation of HO-1-null mice (30, 31) were important events in investigating the role of HO-1 in the regulation of blood pressure. Sabaawy et al. have shown recently that a single intracardiac injection of a retroviral vector containing human HO-1 was able to produce transgene overexpression in the kidney, liver, heart, lung, and brain (29). This overexpression of HO-1 was associated with an increase in HO enzyme activity and a decrease in blood pressure in spontaneously hypertensive rats (29). Rats overexpressing the HO-1 transgene also showed a reduction in myogenic responses to increased intraluminal pressure in isolated arterioles. These data confirmed the importance of HO-1 in attenuating the development of hypertension in an animal model. Interestingly, a recent report (32) suggested that transgenic overexpression of HO-1 using the SM22- promoter might elevate blood pressure in mice. Because the ability of CO to activate soluble guanylate cyclase and increase cGMP is less than nitric oxide (NO), it was felt that the overproduction of CO in these transgenic mice might impair the NO-elicited increase in cGMP. Because expression of the SM22- promoter occurs mainly in large- and medium-sized vessels, one may hypothesize that the difference in responses to HO-1 overexpression may depend on the exact site of transgene expression within the vascular tree (larger vessels versus smaller vessels and arterioles).

We have also investigated the regulation of blood pressure in HO-1-deficient mice. We demonstrated previously that no difference in systolic blood pressure was evident between HO-1^+/+, HO-1^+/-, and HO-1^-/- mice at baseline (Fig. 1a, white bars). These data revealed that different from the acute inhibition of HO enzymes in normal animals (18), the chronic absence of HO-1 does not lead to a sustained increase in systolic blood pressure (33). This may suggest a role for HO-2 in blood pressure regulation in the setting of acute HO inhibition or that during the chronic absence of HO-1 compensatory mechanisms prevent an increase in systolic blood pressure.

View larger version (18K): [in this window] [in a new window]   Figure 1. Effect of HO-1 deficiency on the development of renovascular hypertension and acute renal function. (a) Systolic blood pressure was measured using a tail-cuff method 9 weeks after 1K1C (black bars) or sham (white bars) surgery in HO-1+/+, HO-1+/-, and HO-1-/- mice. n = 4 to 5 mice/genotype in each surgical group. *P < 0.05 versus sham controls, and P < 0.05 versus all other groups. (b) Twenty-eight hours after surgery, mice were killed and plasma was collected. Plasma creatinine concentrations were subsequently measured in HO-1+/- (black bars) and HO-1-/- (white bars) mice after 1K1C (+) or sham (-) surgery. n = 4 in each of the sham HO-1+/- and HO-1-/- groups, and n = 8 in each of the 1K1C HO-1+/- and HO-1-/- groups. *P < 0.05 versus all other groups. Adapted from Wiesel et al. (33), with permission.

In mice that are wild type or heterozygous for HO-1, renal artery clipping led to an induction of HO-1 mRNA, and increased HO-1 protein was localized to the renal tubules (33). In the setting of this HO-1 induction, ischemia induced by the renal artery clipping was not severe enough to cause an acute increase in plasma creatinine levels (Fig. 1b, black bars) or structural damage to the kidney. However, in the absence of HO-1, mice subjected to the same clipping experienced increased mortality, increased plasma creatinine levels (Fig. 1b, white bars), and ischemic damage to the renal tubules of the outer medulla (33). By administering an antagonist to the ET_A receptor, the increase in plasma creatinine and the ischemic damage were prevented. Taken together, these data suggested that in the absence of HO-1 and the presence of increased renal ET-1, kidneys are at increased risk for acute ischemic damage and subsequent failure, leading to death (33). Because the 1K1C model of renovascular hypertension is a volume-dependent process initiated by a limitation in renal function, we believe that the exacerbated hypertension in HO-1^-/- mice reflects progressive renal injury contributed to by elevated levels of renal ET-1.

Hypotension.
Sepsis is a disease process caused by a severe underlying infection (36–38). The release of bacterial cell wall-derived lipopolysaccharide (LPS or endotoxin) and the subsequent production of inflammatory cytokines and vasoactive mediators contribute to vascular smooth muscle cell relaxation and a reduction in blood pressure. If left unchecked, this process may progress to refractory hypotension, multiple organ system failure, and death. We have previously demonstrated that interleukin (IL)-1ß and LPS markedly induce HO-1 expression in cultured vascular smooth muscle cells and several organs of endotoxemic rats, respectively (39, 40), suggesting that HO-1 may be involved in the pathogenesis of endotoxic shock. Immunohistochemical staining also localized an increase in HO-1 protein within smooth muscle and endothelial cells of both large (aorta) and small (arterioles) blood vessels (39). We have also demonstrated that Zn-protoporphyrin IX, an inhibitor of HO activity, abrogates endotoxin-induced hypotension in rats (39). These results implied that the marked induction of HO-1 during endotoxemia contributed to the decrease in systemic blood pressure.

To better understand the role of HO-1 in the pathophysiology of endotoxemia, we evaluated LPS-induced hypotension and end-organ dysfunction in HO-1 deficient (HO-1^-/-) mice (41). The goal of this study was to define the role of HO-1 in LPS-induced hypotension and to determine whether refractory hypotension and/or exaggerated oxidative stress was responsible for the mortality in HO-1^-/- mice. In this study, systolic blood pressure was measured before and after the administration of LPS to HO-1^+/+, HO-1^+/-, and HO-1^-/- mice. Four hours after LPS, systolic blood pressure was reduced in mice from all three groups. However, systolic blood pressure was significantly increased after 24 hr in HO-1^-/- mice compared with HO-1^+/+ and HO-1^+/- mice (Fig. 2a). Even though systolic blood pressure was higher in HO-1^-/- mice that survived the LPS challenge, we found increased mortality in the group (41). These data demonstrate, for the first time, that HO-1 contributes to the sustained hypotension associated with endotoxemia, and that a lack of HO-1 results in increased mortality that is not associated with intractable hypotension.

View larger version (19K): [in this window] [in a new window]   Figure 2. Effect of HO-1 deficiency on systolic blood pressure and tissue oxidative damage. (a) Baseline systolic blood pressure was measured in HO-1+/+ (black circles, n = 10), HO-1+/- (black triangles, n = 8), and HO-1-/- (white circles, n = 8) mice. The mice were injected with LPS (5 mg/kg ip), and systolic blood pressure was subsequently measured 4 and 24 hr after the LPS. *P < 0.05 versus HO-1+/+ and HO-1+/- groups. (b) HO-1+/+ (black bars) and HO-1-/- (white bars) mice were injected with vehicle (-, n = 3 in each group) or LPS (+, 5 mg/kg, n = 3 in each group) intraperitoneally. The mice were killed 24 hr after LPS administration, and lipid peroxidation products (MDA and 4-HNE) were measured in liver homogenates. *P < 0.05 versus vehicle treated HO-1+/+ group, P < 0.05 versus all other groups. Adapted from Wiesel et al. (41), with permission.

The development of multiple organ failure is a key predictor of outcome in septic patients. Thus, we examined the mice for LPS-induced end-organ damage. After LPS stimulation, hepatic and renal dysfunction was noted in HO-1^-/-, but not HO-1^+/+ and HO-1^+/- mice (41). These data show LPS-induced hepatocellular damage and renal dysfunction only in mice lacking HO-1.

The absence of HO-1–induced CO and the sustained induction of ET-1 may have contributed to end-organ damage because of oxidative damage, resulting from excessive vasoconstriction and decreased tissue perfusion. Furthermore, decreased generation of bilirubin (an important antioxidant), and iron deposition provide an environment susceptible to oxidative stress and damage in the absence of HO-1. The administration of LPS to wild-type mice caused a 3-fold increase in lipid peroxidation products in liver tissue (malondialdehyde and 4-hydroxy-2-nonenal, Fig. 2b, black bars), which is consistent with increased oxidative stress associated with endotoxemia. In HO-1^-/- mice, however, lipid peroxidation products were increased 7-fold after the administration of LPS (Fig. 2b, white bars). This level of lipid peroxidation products in HO-1^-/- mice was significantly higher than wild-type mice. These data suggest that the increased mortality during endotoxemia in HO-1^-/- mice is related to increased oxidative stress and end-organ damage, not to refractory hypotension (41). Taken together, these results suggest that while an exaggerated induction of HO-1 may participate in the hypotensive response to LPS, basal HO-1 expression is needed to resist oxidative stress.

HO-1 and Cardiac Function

Our laboratory previously generated HO-1-null mice and subjected them to chronic hypoxia for 5 to 7 weeks. We found that the HO-1^-/- mice had premature mortality compared with HO-1^+/+ mice and that their death was associated with right ventricular dilation, right ventricular infarcts, and organized mural thrombi on the surface of the infarcts (31). Right ventricular cardiomyocytes also showed evidence of increased oxidative damage in HO-1^-/- mice, leading us to propose that HO-1 may play a central role in cardiac physiology by protecting cardiomyocytes from pressure-induced injury and secondary oxidative damage.

The generation of reactive oxygen species in the heart, caused by ischemia and reperfusion, is the major reason for postischemic myocardial injury (42). Based upon the evidence for cytoprotection provided by HO-1 against oxidative damage, we proposed that HO-1 might confer protection from myocardial ischemia and reperfusion damage. Thus, we next generated cardiac-specific transgenic mice overexpressing different levels of human HO-1 under the control of the -myosin heavy chain promoter. Using an isolated-perfused heart preparation, we demonstrated that hearts from transgenic mice showed improved functional recovery (diastolic and systolic) during a postischemic reperfusion period in an HO-1 dose-dependent manner (43). Recently, the above results have been corroborated by Vulapalli et al. (44). In addition to better cardiac function, after ischemia and reperfusion of the left anterior descending coronary artery in vivo, our HO-1 transgenic mice also showed a marked reduction in left ventricular infarct size (Fig. 3) and a reduction in inflammatory cell infiltrates and oxidative damage compared with wide-type mice (43). The production of CO and bilirubin via the HO system has been shown to be important protective factors in myocardial ischemia/reperfusion injury. Bilirubin at physiological levels can provide cardioprotection by suppressing oxidation of lipid membranes (11) and preventing endothelial cell death caused by hydrogen peroxide (45). Several studies have demonstrated that low serum bilirubin levels correlate with an increased risk for developing ischemic heart disease (46, 47). Clark et al. also found that exogenously administrated bilirubin significantly improved cardiac function and decreased myocardial infarct size and mitochondrial damage upon reperfusion insult (48). In addition, the suppression of stress-mediated acute hypertensive responses by CO in vascular smooth muscle cells may contribute to the cardioprotection of HO-1 (49). Other cardioprotective effects of CO, as demonstrated using a mouse-to-rat cardiac transplant model, include the inhibition of endothelial cell apoptosis, platelet aggregation, and vascular thrombosis (50). Moreover, ferritin, which is induced by oxidative insults and sequesters iron generated during heme catabolism, may serve to protect against ischemia-reperfusion injury via its cytoprotective effect in the vascular endothelium (51) and its ability to keep labile iron pools low and thereby reduce oxidant-induced chain reactions involving lipid peroxidation (52). Another complication of reperfusion injury is cardiac arrhythmias. Pataki et al. have shown that the development of reperfusion-induced ventricular fibrillation inhibits HO-1 mRNA expression and enzyme activity in the heart (53), suggesting that overexpression of HO-1 may prevent this potentially lethal arrhythmia.

View larger version (17K): [in this window] [in a new window]   Figure 3. HO-1 protects against myocardial infarctions in transgenic mice. Wild-type (WT) mice (white bars, n = 6) and transgenic (TG) mice (black bars, n = 8) were subjected to 1 hr of ischemia and 24 hr of reperfusion. Risk area/LV indicates percentage of left ventricle at risk. Infarct/risk area indicates infarcted area as a percentage of the total LV area at risk. Error bars indicate SE. *P = 0.001 versus infarct/risk area of WT mice. Adapted from Yet et al. (43), with permission.

Summary

Ample evidence has been provided to support HO-1 as a key component in various cardiovascular disease processes. In this article, we have highlighted the role of HO-1 in renovascular hypertension, endotoxemia-induced hypotension and multiple organ dysfunction, and coronary artery ischemia/reperfusion injury. The previously mentioned studies in this article underscore the potential for HO-1 as a therapeutic target for diseases of the cardiovascular system. However, the effect of HO-1 on these disease processes may vary depending on the level of expression, and the exact location (specific cell-type or organ) of expression. Thus, a key to future studies will be to properly target and regulate HO-1 expression in a cell-type specific fashion to allow maximal cytoprotection at the site of a pathophysiologic process.

Footnotes

This work was supported by the National Institutes of Health Grants GM53249 and HL60788 (to M. A. P.) and grants from the American Heart Association and American Diabetes Association (to S.-F. Y.).

¹ To whom requests for reprints should be addressed at Pulmonary and Critical Care Division, Brigham and Women’s Hospital, 75 Francis St. TH1127A, Boston, MA 02115. E-mail: mperrella{at}rics.bwh.harvard.edu

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