Increased HO-1 expression and decreased iNOS expression in the hippocampus from adult spontaneously hypertensive rats

Brain expression of heme oxygenase (HO) and nitric oxide synthase (NOS) in hypertension may participate in the pathogenesis of hypertension-related neuronal disorders, such as vascular dementia. In the present study, expression levels of HO and NOS in spontaneously hypertensive rats (SHR) were investigated using Western immunoblotting assay. Expression level of inducible HO-1 in hippocampus of 4-wk prehypertensive SHR was about twofold of that in age-matched Sprague-Dawley (SD) rats (p<0.01). In 23-wk SHR with fully developed hypertension, hippocampal HO-1 level was significantly greater than that of age-matched SD rats (p<0.05), but not different from 4-wk SHR. There was no difference in expression levels of hippocampal HO-2 between SHR and SD rats at different ages. Total enzymatic activity of hippocampal HO was significantly greater in 23-wk SHR than in age-matched SD rats or 4-wk SD/SHR (p<0.01). Although hippocampal expression of nNOS protein was relatively unchanged, iNOS expression in 23-wk SHR was about fourfold lower than that in age-matched SD rats and 4-wk SD/SHR (p<0.01). Total enzymatic activity of hippocampal NOS was significantly lower in 23-wk SHR than in age-matched SD rats or 4-wk SD/SHR (p<0.01). Significantly suppressed Morris water maze performance was found in 23-wk SHR in comparison with age-matched SD rats. Because SHR has been used as a model of vascular dementia and hippocampus is essential for spatial learning and memory, understanding of altered HO/CO and NOS/NO systems in the hippocampus of adult SHR may shed light on the pathogenic development of memory deficits associated with vascular dementia.     

Hydrogen Sulfide and Carbon Monoxide Are in Synergy with Each Other in the Pathogenesis of Recurrent Febrile Seizures

1. The purpose of the present study was to investigate the interaction between hydrogen sulfide (H(2)S) and carbon monoxide (CO) during recurrent febrile seizures (FS) 2.H(2)S and CO are important intra- and intercellular messengers, regulating various brain functions. Our recent studies showed that both of them alleviate the hippocampal damage induced by recurrent FS. In the present study, on a rat model of recurrent FS, we found that hydroxylamine (an inhibitor of cystathionine b-synthase, CBS) reduced CO level and down regulated heme oxygenase (HO-1) expression, while NaHS (a donor of H(2)S) elevated CO level and upregulated HO-1 expression. ZnPP-IX (an inhibitor of HO-1) decreased H(2)S formation and down regulated CBS expression, while hemin (which increases the production of endogenous CO) enhanced H(2)S formation and elevated CBS expression. 3.Our data demonstrate that endogenous H(2)S and CO are in synergy with each other in recurrent FS.     

A new antioxidant compound H-290/51 attenuates nitric oxide synthase and heme oxygenase expression following hyperthermic brain injury

Influence of a new anti-oxidant compound H-290/51 on expression of nitric oxide synthase (NOS) and heme oxygenase (HO) enzymes responsible for nitric oxide (NO) and carbon monoxide (CO) production, respectively was examined in the CNS following heat stress in relation to cell injury. Exposure of rats to 4h heat stress at 38 degrees C in a biological oxygen demand (BOD) incubator (relative humidity 50-55%, wind velocity 20-25cm/sec) resulted in profound edema and cell injury in many parts of the cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus and brain stem. Immunostaining of constitutive isoforms of neuronal NOS (nNOS) and HO-2 revealed marked upregulation in damaged and distorted neurons located within the edematous brain regions. Pretreatment with H-290/51 (50 mg/kg, p.o., 30 min before heat stress) significantly reduced the edematous swelling and cell injury and resulted in a marked attenuation of nNOS and HO-2 expression. These observations suggest that upregulation of NOS and HO is associated with cell injury, and the antioxidant compound H-290/51 is neuroprotective in heat stress.     

The regulating effect of heme oxygenase/carbon monoxide on hypoxic pulmonary vascular structural remodeling

Hypoxic pulmonary vascular structural remodeling (HPVSR) is the important pathologic basis of hypoxic pulmonary hypertension (HPH). The discoveries of endogenous gaseous messenger molecules, nitric oxide (NO) and carbon monoxide (CO), have been moving the research of HPVSR to a very new phase. But the effect and significance of heme oxygenase (HO)/CO on the development of HPVSR have not been fully understood. In this study, we observed the alteration of endogenous HO/CO system in five time points during 14 days and found that the content of CO in lung homogenates in rats with HPVSR increased in a time-dependent double-peak manner. Exogenous supply of ZnPP-IX, an inhibitor of HO-1, decreased the content of CO in lung homogenate, decreased the expression of Fas and apoptotic cells in pulmonary artery smooth muscle cells (PASMCs), up-regulated the expression of PCNA in PASMCs, and worsened HPH and HPVSR of hypoxic rats. Meanwhile, exogenous supply of CO played an adverse action. The results showed that the up-regulation of HO/CO exerted a protective role in the development of HPVSR.     

Hydrogen sulfide may improve the hippocampal damage induced by recurrent febrile seizures in rats

The aim of the present study was to investigate the possible role of hydrogen sulfide (H(2)S) in the pathogenesis of recurrent febrile seizures (FS) in rats. On a rat model of recurrent FS, the ultrastructure of hippocampal neurons, the plasma level of H(2)S, the expressions of cystathionine b-synthase (CBS) and c-fos, and the development of mossy fiber sprouting (MFS) in hippocampus were examined after treatment with NaHS, a donor of H(2)S, or hydroxylamine (HA), an inhibitor of CBS. We found that the plasma level of H(2)S increased significantly, the expressions of CBS and c-fos increased markedly, and MFS was evident in hippocampus in FS group. NaHS alleviated the neuronal damage of recurrent FS rats, decreased the expression of c-fos, and inhibited MFS obviously. HA aggravated the neuronal damage of recurrent FS rats, further increased the expression of c-fos, and enhanced the mossy fiber outgrowth. The results showed that endogenous H(2)S system was involved in the development of FS. Exogenous H(2)S may exert beneficial effect on the pathogenesis of FS-related brain damage.     

The regulatory effect of endogenous hydrogen sulfide on pulmonary vascular structure and gasotransmitters in rats with high pulmonary blood flow

The study aimed to explore the regulatory effect of endogenous hydrogen sulfide (H(2)S), a novel gasotransmitter, on pulmonary vascular structure and gasotransmitters in rats with high pulmonary blood flow. Thirty-two Sprague-Dawley rats were randomly divided into a sham group, shunt group, sham+PPG (propargylglycine, an inhibitor of cystathionine-gamma-lyase) group and shunt+PPG group. Rats in the shunt and shunt+PPG groups underwent abdominal aorta-inferior vena cava shunting. Rats in the shunt+PPG and sham+PPG groups were intraperitoneally injected with PPG. After 4 weeks of shunting, mean pulmonary artery pressure (MPAP) and pulmonary vascular structural remodeling (PVSR) were evaluated. H(2)S, nitric oxide (NO) and carbon monoxide (CO) contents were measured in lung tissues. Meanwhile, nitric oxide synthase (eNOS), heme oxygenase (HO-1) and proliferative cell nuclear antigen (PCNA) protein expressions and ERK activation were evaluated. After 4 weeks of shunting, rats showed PVSR with increased lung tissue H(2)S and NO content but decreased CO content. After the PPG treatment, MPAP further increased and PVSR was aggravated. Meanwhile, PCNA expression and ERK activation were augmented with decreased lung tissue CO and HO-1 protein production but increased lung tissue NO production and eNOS expression. H(2)S exerted a protective effect on PVSR, and the inhibition of the NO/NOS pathway and the augmentation of the CO/HO pathway might be involved in the mechanisms by which H(2)S regulates PVSR in rats with high pulmonary flow.     

Neuronal Overexpression of Heme Oxygenase-1 Correlates with an Attenuated Exploratory Behavior and Causes an Increase in Neuronal NADPH Diaphorase Staining

Abstract: Heme oxygenase isozymes, HO-1 (also known as hsp32) and HO-2, are the source for the formation of the putative messenger molecule carbon monoxide (CO), reactive iron, and the in vitro antioxidant bilirubin. We have developed and characterized transgenic (Tg) mice that overexpress the stress protein in neurons in various brain regions. The Tg mice were generated by the use of rat HO-1 cDNA under the control of the neuron-specific enolase promoter. Except for a tendency to have an enlarged spleen, Tg mice did not show gross anatomical changes. Increase in HO-1 mRNA, which was demonstrated by northern blot analysis and in situ hybridization, was accompanied by an increase in neuronal HO-1 protein expression, shown by immunohistochemistry and western blotting, and an increase in HO activity. Expression of the transgene correlated with an attenuation of exploratory behavior and increased circling activity and coincided with enhanced neuronal NADPH diaphorase staining. Those changes were not accompanied by an increase in DNA damage or significant change in whole-brain NO synthase activity. The HO-1 Tg mice potentially represent a good model to examine the function of CO as a neuromodulator, iron as a gene regulator, and bile pigments as in vivo antioxidants.     

Corticosterone Has a Permissive Effect on Expression of Heme Oxygenase-1 in CA1–CA3 Neurons of Hippocampus in Thermal-Stressed Rats

Abstract: Activity of the stress protein, heme oxygenase-1 (hsp32; HO-1), produces carbon monoxide (CO), the potential messenger molecule for excitatory N -methyl- d -aspartate receptor-mediated events, in the hippocampus. Long-term stress caused by elevated adrenocorticoids induces pathological changes in CA1–CA3 neurons, of the hippocampus; the adrenal hormones also exacerbate damage from stress. In rats chronically treated with corticosterone, we examined expression of HO-1 and its response to thermal stress in the hippocampus. An unprecedented appearance of scattered immunoreactive astrocytes marked the molecular layer of the hippocampus in corticosterone-treated rats. Steroid treatment showed no discernible effect on whole-brain HO-1 mRNA. When these rats were subjected to hyperthermia, neurons in the CA1–CA3 area, including pyramidal cells, exhibited intense immunoreactivity for the oxygenase and a pronounced increase (∼10-fold) in number. HO-1 is essentially undetectable in this area when rats are exposed to chronic corticosterone alone or thermal stress by itself, or in control rats. In contrast, similar analysis of hilar neurons showed no apparent effect on either the number or relative intensity of HO-1-immunostained cells after treatment. Corticosterone treatment also intensified the stress response of cerebellum, including Purkinje cells and Bergmann glia in the molecular layer. In brain, despite a pronounced reduction in NO synthase activity in corticosterone-treated and/or heat-stressed animals, the level of cyclic GMP was not significantly reduced. These observations are consistent with the hypothesis that responsiveness to environmental stress of CA1–CA3 neurons brought about by chronic elevation in circulating adrenocorticoids results in an increased excitatory neuronal activity and eventual hippocampal degeneration. Moreover, these findings yield further support for a role of CO in the production of cyclic GMP in the brain.     

Heme oxygenase-2 distribution in anorectum: colocalization with neuronal nitric oxide synthase

Recent investigations have suggested carbon monoxide (CO) as a putative messenger molecule. Although several studies have implicated the heme oxygenase (HO) pathway, responsible for the endogenous production of CO, in the neuromodulatory control of the internal anal sphincter (IAS), its exact role is not known. Nitric oxide, produced by neuronal nitric oxide synthase (nNOS) of myenteric neurons, is an important inhibitory neural messenger molecule mediating nonadrenergic noncholinergic (NANC) relaxation of the IAS. The present studies were undertaken to investigate in detail the presence and coexistence of heme oxygenase-2 (HO-2) with nNOS in the opossum anorectum. In perfusion-fixed, frozen-sectioned tissue, HO-2 immunoreactive (IR) and nNOS IR nerves were identified using immunocytochemistry. Ganglia containing HO-2 IR neuronal cell bodies were present in the myenteric and submucosal plexuses throughout the entire anorectum. Colocalization of HO-2 IR and nNOS IR was nearly 100% in the IAS and decreased proximally from the anal verge. In the rectum, colocalization of HO-2 IR and nNOS IR was approximately 70%. Additional confocal microscopy studies using c-Kit staining demonstrated the localization of HO-2 IR and nNOS IR in interstitial cells of Cajal (ICC) of the anorectum. From the high rate of colocalization of HO-2 IR and nNOS IR in the IAS as well as the localization of HO-2 IR and nNOS IR in ICC in conjunction with earlier studies of the HO pathway, we speculate an interaction between HO and NOS pathways in the NANC inhibitory neurotransmission of the IAS and rectum.     

内源性一氧化碳与一氧化氮在高血压发病中的相互作用 …

目的和方法：采用ＨＯ活性抑制剂诱导大鼠高血压模型,观察血压变化、主动脉ＨＯ和ＮＯＳ活性、ＣＯ和ＮＯ产生释放,并测定血浆和主动脉平滑肌组织中ｃＧＭＰ含量,以探讨内源性ＮＯ和ＣＯ在高血压发生机制中的作用及其相互关系。结果：大鼠应用ＨＯ抑制剂ＺｎＤＰＢＧ腹腔注射２周后,继续饲养到第４周出现持续而稳定的高血压,同时总ＮＯＳ（ｔＮＯＳ）和诱导型ＮＯＳ（ｉＮＯＳ）的活性分别增加４５．４％和７３．３％（均为Ｐ〉     

Inhibition of heme oxygenase augments tubular sodium reabsorption

Heme oxygenase (HO) catalyzes the degradation of heme to form iron, biliverdin, and carbon monoxide (CO). The vascular actions of CO include direct vasodilation of vascular smooth muscle and indirect vasoconstriction through inhibition of nitric oxide synthase (NOS). This study was performed to examine the effects in the kidney of inhibition of heme oxygenase alone or combined with NOS inhibition. Chromium mesoporphyrin (CrMP; 45 μmol/kg ip), a photostable HO inhibitor, was given to control rats and N(G)-nitro-l-arginine methyl ester (l-NAME)-treated hypertensive rats (50 mg·kg?1·day?1), 12 h, 4 days). In control animals, CrMP decreased CO levels, renal HO-1 levels, urine volume, and sodium excretion, but had no effect on arterial pressure, renal blood flow (RBF), plasma renin activity (PRA), or glomerular filtration rate (GFR). In l-NAME-treated hypertensive rats, CrMP decreased endogenous CO and renal HO-1 levels and had no effect on arterial pressure, RBF, or GFR but decreased sodium and water excretion in a similar manner to control animals. An increase in PRA was observed in untreated rats but not in l-NAME-infused rats, indicating that this effect is associated with an absent NO system. The results suggest that inhibition of HO promotes water and sodium excretion by a direct tubular action that is independent of renal hemodynamics or the NO system.     

Carbon monoxide mediates heme oxygenase 1 induction via Nrf2 activation in hepatoma cells

Carbon monoxide (CO) and nitric oxide (NO) are two gas molecules which have cytoprotective functions against oxidative stress and inflammatory responses in many cell types. Currently, it is known that NO produced by nitric oxide synthase (NOS) induces heme oxygenase 1 (HO1) expression and CO produced by the HO1 inhibits inducible NOS expression. Here, we first show CO-mediated HO1 induction and its possible mechanism in human hepatocytes. Exposure of HepG2 cells or primary hepatocytes to CO resulted in dramatic induction of HO1 in dose- and time-dependent manner. The CO-mediated HO1 induction was abolished by MAP kinase inhibitors (MAPKs) but not affected by inhibitors of PI3 kinase or NF-kappaB. In addition, CO induced the nuclear translocation and accumulation of Nrf2, which suppressed by MAPKs inhibitors. Taken together, we suggest that CO induces Nrf2 activation via MAPKs signaling pathways, thereby resulting in HO1 expression in HepG2 cells.     

Pro-oxidant Role of Heme Oxygenase in Mediating Glucose-induced Endothelial Cell Damage

Oxidative damage to the vascular endothelial cells may play a crucial role in mediating glucose-induced cellular dysfunction in chronic diabetic complications. The present study was aimed at elucidating the role of glucose-induced alteration of highly inducible heme oxygenase (HO) in mediating oxidative stress in the vascular endothelial cells. We have also investigated the interaction between HO and the nitric oxide (NO) system, and its possible role in alteration of other vasoactive factors.

Human umbilical vein endothelial cells (HUVECs) were exposed to low (5?mmol/l) and high (25?mmol/l) glucose levels. In order to determine the role of HO in endothelial dysfunction and to elucidate a possible interaction between the HO and NO systems, cells were exposed to HO inducer (hemin, 10?μmol/l), HO antagonist (SnPPIX, 10?μmol/l), and NO synthase blocker (l-NAME, 200?μmol/l) with or without NO donor (arginine, 1?mmol/l). mRNA expression of HO and NO isoforms was measured by real time RT-PCR. HO activity was measured by bilirubin production and cellular oxidative stress was assessed by 8-hydroxy-2′-deoxyguanosine (8-OHdG) and nitrotyrosine staining. We also determined the expression of vasoactive factors, endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF).

In the endothelial cells, glucose caused upregulation of HO-1 expression and increased HO activity. A co-stimulatory relationship between HO and NO was observed. Increased HO activity also associated with oxidative DNA and protein damage in the endothelial cells. Furthermore, increased HO activity augmented mRNA expression of vasoactive factors, ET-1 and VEGF. These data suggest that HO by itself and via elaboration of other vasoactive factors may cause endothelial injury and functional alteration. These findings are of importance in the context of chronic diabetic complications.     

内源性一氧化碳在大鼠高血压发病中的作用

本实验研究内源性血红素氧化酶／一氧化碳系统在大鼠高血压发病听作用。２,４二甘油次卟啉锌是体内ＨＯ活必抑制剂 。     

性激素对血红素氧化酶在大鼠前列腺腹侧叶表达的影响

血红素氧化酶(heme oxygenase,HO)是产生内源性一氧化碳(carbon monoxide,CO)的限速酶,最近发现内源性CO在调节平滑肌张力方面起重要作用。而人的良性前列腺增生(benign prostates hyperplasia,BPH)所致的膀胱出口梗阻与前列腺平滑肌张力有密切关系,但还不清楚内源性HO/CO系统是否介导了前列腺平滑肌的活动。为了观察性激素对大鼠前列腺腹侧叶中血红素氧化酶-1(heme oxygenase-1,HO-1)和血红素氧化酶-2(heme oxygenase-2,HO-2)基因表达的影响,我们采用睾丸切除术建立雄性SD大鼠去势模型,用RT-PCR方法观察HO-1和HO-2的转录水平,应用免疫组织化学结合图像分析技术,观察去势、外源性雄激素和雌激素对前列腺腹侧叶中HO—1和HO-2蛋白水平的影响。结果表明,HO-1和HO-2在正常大鼠前列腺腹侧叶中都有表达,腺上皮细胞和纤维平滑肌间质呈现HO-1的免疫活性,HO-2的免疫染色仅在腺上皮细胞内检测到;去势组HO-1的mRNA和蛋白表达水平显著低于正常对照组(P<0.01):外源性给予雄激素组和雌激素组的HO-1表达水平明显增高(P<0.01),且雌激素主要增加前列腺纤维平滑肌间质的HO-1表达:HO-2在各组间的表达无明显差异(P>0.05)。这些结果提示,性激素对HO-1有诱导作用,但对HO-2无明显的影响,因此推测一氧化碳-血红素氧化酶(CO—HO)     

Neuronal and Endothelial Nitric Oxide Synthases in the Paraventricular Nucleus Modulate Sympathetic Overdrive in Insulin-Resistant Rats

A central mechanism participates in sympathetic overdrive during insulin resistance (IR). Nitric oxide synthase (NOS) and nitric oxide (NO) modulate sympathetic nerve activity (SNA) in the paraventricular nucleus (PVN), which influences the autonomic regulation of cardiovascular responses. The aim of this study was to explore whether the NO system in the PVN is involved in the modulation of SNA in fructose-induced IR rats. Control rats received ordinary drinking water, whereas IR rats received 12.5% fructose-containing drinking water for 12 wks to induce IR. Basal SNA was assessed based on the changes in renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in response to chemicals administered to the PVN. We found an increased plasma norepinephrine level but significantly reduced NO content and neuronal NOS (nNOS) and endothelial NOS (eNOS) protein expression levels in the PVN of IR rats compared to Control rats. No difference in inducible NOS (iNOS) protein expression was observed between the two groups. In anesthetized rats, the microinjection of sodium nitroprusside (SNP), an NO donor, or Nω-nitro-L-arginine methyl ester (L-NAME), a non-selective inhibitor of NOS, into the PVN significantly decreased and increased basal SNA, respectively, in both normal and IR rats, but these responses to SNP and L-NAME in IR rats were smaller than those in normal rats. The administration of selective inhibitors of nNOS or eNOS, but not iNOS, to the PVN significantly increased basal SNA in both groups, but these responses were also smaller in IR rats. Moreover, IR rats exhibited reduced nNOS and eNOS activity in the PVN. In conclusion, these data indicate that the decreased protein expression and activity levels of nNOS and eNOS in the PVN lead to a reduction in the NO content in the PVN, thereby contributing to a subsequent enhancement in sympathoexcitation during IR.     

Guanosine stimulates neurite outgrowth in PC12 cells via activation of heme oxygenase and cyclic GMP

Undifferentiated rat pheochromocytoma (PC12) cells extend neurites when cultured in the presence of nerve growth factor (NGF). Extracellular guanosine synergistically enhances NGF-dependent neurite outgrowth. We investigated the mechanism by which guanosine enhances NGF-dependent neurite outgrowth. Guanosine administration to PC12 cells significantly increased guanosine 3,5-cyclic monophosphate (cGMP) within the first 24 h whereas addition of soluble guanylate cyclase (sGC) inhibitors abolished guanosine-induced enhancement of NGF-dependent neurite outgrowth. sGC may be activated either by nitric oxide (NO) or by carbon monoxide (CO). -Nitro-l-arginine methyl ester (l-NAME), a non-isozyme selective inhibitor of nitric oxide synthase (NOS), had no effect on neurite outgrowth induced by guanosine. Neither nNOS (the constitutive isoform), nor iNOS (the inducible isoform) were expressed in undifferentiated PC12 cells, or under these treatment conditions. These data imply that NO does not mediate the neuritogenic effect of guanosine. Zinc protoporphyrin-IX, an inhibitor of heme oxygenase (HO), reduced guanosine-dependent neurite outgrowth but did not attenuate the effect of NGF. The addition of guanosine plus NGF significantly increased the expression of HO-1, the inducible isozyme of HO, after 12 h. These data demonstrate that guanosine enhances NGF-dependent neurite outgrowth by first activating the constitutive isozyme HO-2, and then by inducing the expression of HO-1, the enzymes responsible for CO synthesis, thus stimulating sGC and increasing intracellular cGMP.     

Regulation of heme oxygenase-1 by nitric oxide during hepatopulmonary syndrome

During hepatopulmonary syndrome caused by liver cirrhosis, pulmonary endothelial nitric oxide (NO) synthase (NOS) expression and NO production are increased. Increased NO contributes to the blunted hypoxic pressor response (HPR) during cirrhosis and may induce heme oxygenase-1 (HO-1) expression and carbon monoxide (CO) production, exacerbating the blunted HPR. We hypothesized that NO regulates the expression of HO-1 during cirrhosis, contributing to hepatopulmonary syndrome. Cirrhosis was induced in rats by common bile duct ligation (CBDL). Rats were studied 2 and 5 wk after CBDL or sham surgery. Lung HO-1 expression was elevated 5 wk after CBDL. Liver HO-1 was increased at 2 wk and remained elevated at 5 wk. In catheterized rats, the blunted HPR was partially restored by HO inhibition. Rats treated with the NOS inhibitor N(G)-nitro-L-arginine methyl ester for the entire 2- or 5-wk duration had normalized HO-1 expression and HPR. These data provide in vivo evidence for the NO-mediated upregulation of HO-1 expression and support the concept that hepatopulmonary syndrome is multifactorial, involving not only NO, but also HO-1 and CO.     

血红素氧合酶-1/一氧化碳通路参与辛伐他汀抗高血压诱发的大鼠心肌肥厚

为了探讨他汀类药物抑制心肌肥厚的作用机制,本研究应用一氧化氮合酶抑制剂左旋硝基精氨酸[N-nitro-L-arginine, L-NNA,15 mg／(kg·d)]制备大鼠高血压心肌肥厚模型,并分别给予不同剂量辛伐他汀[5或30 mg／(kg·d)进行干预。6周后测大鼠左心室功能、左心室重量指数(left ventricular mass index,LVMI)、心肌脑钠素(brain natriuretic peptide,BNP)含量、心肌羟脯氨酸含量和心肌血红素氧合酶(heme oxygenase,HO)活性。在体外培养的新生大鼠心肌细胞中,观察辛伐他汀对血管紧张素Ⅱ(angiotensin Ⅱ,Ang Ⅱ)引起的心肌细胞肥大的抑制作用与细胞血红素氧合酶-1(HO-1)表达、HO活性及CO生成间的关系。结果表明,辛伐他汀干预明显减轻L-NNA处理大鼠的心肌肥厚(LVMI值、心肌BNP和羟脯氨酸含量均显著低于单纯L-NNA处理组),改善左心室舒张功能,而且心肌HO活性显著升高。在离体培养的原代乳鼠心肌细胞,辛伐他汀浓度依赖性地抑制Ang Ⅱ引起的细胞肥大(3H-亮氨酸掺入),并相应增加HO-1 mRNA表达、HO活性和CO生成量。应用HO抑制剂锌卟啉能有效抑制辛伐他汀抗Ang Ⅱ诱导的心肌肥大作用。结果提示:辛伐他汀上调HO-1／CO通路是其抗高血压诱发的心肌肥厚的机制之一。