Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats

Ndisang, Joseph Fomusi; Wu, Lingyun; Zhao, Weiqi; Wang, Rui

doi:10.1182/blood-2002-08-2608

Cited by 84 publications

(74 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…HO activity in the soleus muscle was measured as bilirubin production using our established method (27,47,49). Briefly, the soleus muscle were homogenized on ice in 4 vol of 5:1 K/Na 100 mmol/l phosphate buffer (pH 7.4) with 2 mmol/l MgCl2 (HO-activity buffer) and centrifuged at 13,000 rpm for 15 min.…”

Section: Determination Of Ho Activity and Ho-1 Concentration In The Smentioning

confidence: 99%

“…The concentration of cGMP was assessed by enzyme immunoassay (EIA; Cayman Chemical, Ann Arbor, MI) as we previously described (27,47,49). Briefly, the soleus muscles were homogenized in 6% TCA at 4°C in the presence of IBMX to inhibit phosphodiesterase activity and were centrifuged at 2,000 g for 15 min.…”

Section: Determination Of Insulin Resistance By Homeostasis Model Assmentioning

confidence: 99%

“…The soleus muscle was homogenized with a cocktail of protease inhibitors and centrifuged as we previously described (27,47,49). Briefly, proteins were extracted and quantified by Bradford assay, and aliquots of 50 g were loaded on a 10% SDS-polyacrylamide gel for GSK-3, AMPK, and nitrotyrosine, a marker of oxidative stress (12,30), and 12.5% for GLUT4.…”

Section: Determination Of Insulin Resistance By Homeostasis Model Assmentioning

confidence: 99%

See 2 more Smart Citations

Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes

Ndisang

Lane²,

Jadhav³

2009

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

Ndisang JF, Lane N, Jadhav A. Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes. Am J Physiol Endocrinol Metab 296: E1029-E1041, 2009. First published February 10, 2008 doi:10.1152/ajpendo.90241.2008.-In type 2 diabetes (T2D), postprandial and fasting hyperglycemia are important predictors of cardiovascular diseases; however, few drugs are currently available to simultaneously suppress these conditions. Here, we report an enduring antidiabetic effect of the heme oxygenase (HO) inducer hemin on Goto-Kakizaki rats (GK), a nonobese insulinresistant T2D model. HO breaks down the heme-moiety-generating antioxidants (biliverdin/bilirubin and ferritin) and carbon monoxide, which stimulate insulin secretion. Hemin induces HO-1 to potentiate HO activity and the HO-derived products. Chronically applied hemin (30 mg/kg ip) for a month reduced and maintained fasting glucose at physiological levels for 3 mo. Before therapy, glucose levels were 9.3 Ϯ 0.3 mmol/l (n ϭ 14). At 1, 2, and 3 mo posttherapy, we recorded 6.7 Ϯ 0.13, 5.9 Ϯ 0.2, and 7.2 Ϯ 0.2 mmol/l, respectively. Hemin was also effective against postprandial hyperglycemia (14.6 Ϯ 1.1 vs. 7.5 Ϯ 0.4 mmol/l; n ϭ 14; P Ͻ 0.01), and the effect remained sustained for 3 mo after therapy. The reduction of hyperglycemia was accompanied by enhanced HO-1, HO activity, and cGMP of the soleus muscle, alongside increased plasma bilirubin, ferritin, SOD, total antioxidant capacity, and insulin levels, whereas markers/mediators of oxidative stress like urinary-8-isoprostane and soleus muscle nitrotyrosine, NF-B, and activator protein-1 and -2 were abated. Furthermore, inhibitors of insulin signaling including soleus muscle glycogen synthase kinase-3 and JNK were reduced, while the insulinsensitizing adipokine, adiponectin, alongside AMPK were increased. Correspondingly, hemin improved glucose tolerance, suppressed insulin intolerance, reduced insulin resistance, and overturned the inability of insulin to enhance glucose transporter 4, a protein required for glucose uptake. Hemin also upregulated HO-1/HO activity and cGMP and lowered glucose in euglycemic Sprague-Dawley control rats albeit less intensely, suggesting greater selectivity of the HO system in diabetic conditions. In conclusion, reduced oxidative stress alongside the concomitant and paradoxical enhancement of insulin secretion and insulin-sensitizing pathways may account for the 3-moenduring antidiabetic effect. The synergistic interaction among HO, adiponectin, and GLUT4 may be explored against insulin-resistant diabetes.adiponectin; insulin resistance; oxidative stress; glucose transporter 4; glycogen synthase kinase-3; nuclear factor-B; activating protein-

show abstract

Section: Determination Of Ho Activity and Ho-1 Concentration In The Smentioning

confidence: 99%

Section: Determination Of Insulin Resistance By Homeostasis Model Assmentioning

confidence: 99%

Section: Determination Of Insulin Resistance By Homeostasis Model Assmentioning

confidence: 99%

See 1 more Smart Citation

Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes

Ndisang

Lane²,

Jadhav³

2009

American Journal of Physiology-Endocrinology and Metabolism

Self Cite

View full text Add to dashboard Cite

show abstract

“…Left-ventricular hypertrophy was assessed by left:right ventricular ratio, left-ventricular wall thickness, and left-ventricular body weight index after removing the atria and the right ventricle free wall separated from the left ventricle, including the septum, as described previously. 17 Left-ventricular HO activity was evaluated spectrophotometrically as bilirubin production using our established method, 14,15,18 whereas HO-1 concentration was evaluated by ELISA (Stressgen-Assay Design) and heme by Quantichrom Heme Assay kit (BioAssay Systems). Other biochemical parameters, including urinary/left-ventricular 8-isoprostane, a noninvasive index of oxidative stress, 19 left-ventricular superoxide dismutase (SOD) activity (total), catalase activity, cGMP, and total antioxidant capacity, were measured by EIA (Cayman Chemical).…”

Section: Animal Treatment and Biochemical Assaysmentioning

confidence: 99%

Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

2008

Self Cite

View full text Add to dashboard Cite

Abstract-Deoxycorticosterone acetate-induced hypertension is a volume overload and human primary aldosteronism model characterized by severe cardiac lesions attributed to elevated inflammation, oxidative stress, fibrosis, and hypertrophy. An important cytoprotective pathway that counteracts tissue insults is the heme oxygenase (HO) system. Although the HO-1 gene promoter contains consensus binding sites for proinflammatory/oxidative transcription factors like nuclear factor-B, activating protein (AP)-1, and AP-2, the effects of HO inducers on these transcription factors in cardiac lesions of deoxycorticosterone acetate hypertension are not fully understood. Hemin therapy normalized systolic blood pressure and markedly reduced the left:right ventricular ratio, left ventricular wall thickness, and left ventricle:body weight ratio, whereas the HO blocker, chromium mesoporphyrin, exacerbated cardiac fibrosis/hypertrophy in deoxycorticosterone acetate-hypertensive rats. The cardioprotection by hemin was accompanied by increased HO-1, HO activity, cGMP, superoxide dismutase, catalase, the total antioxidant capacity alongside the reduction of 8-isoprostane, AP-1, AP-2, nuclear factor-B, and c-Jun-NH 2 -terminal kinase, whereas chromium mesoporphyrin abolished the hemin effects. Furthermore, hemin therapy attenuated transforming growth factor-␤ 1 and extracellular matrix proteins like fibronectin and collagen, with a corresponding reduction of histopathologic lesions, including longitudinal/cross-sectional muscle fiber thickness, scarring, muscular hypertrophy, coronary arteriolar thickening, and collagen deposition. The suppression of AP-1, AP-2, nuclear factor-B, and c-Jun-NH 2 -terminal kinase proinflammatory/oxidative mediators in the left ventricle of hemin-treated animals is a novel observation that may account for cardioprotection in deoxycorticosterone acetate hypertension. By concomitantly upregulating HO activity and cGMP and potentiating the total antioxidant status, hemin therapy reduced hypertension, suppressed oxidative stress, and attenuated extracellular matrix and remodeling proteins, with a reduction of histopathologic lesions that characterize cardiac fibrosis, hypertrophy, and end-stage organ damage. (Hypertension. 2008;52:910-917.)Key Words: deoxycorticosterone acetate hypertension Ⅲ heme oxygenase-1 Ⅲ hemin Ⅲ cardiac hypertrophy Ⅲ activating protein-1 Ⅲ nuclear factor B Ⅲ TGF-␤ A ldosterone induces inflammation, oxidative stress, and fibrosis by stimulating nuclear factor-B (NF-B), activating protein (AP), and c-Jun-NH2-terminal kinase (JNK). 1,2 In mineralocorticoid-induced hypertension, the activation of JNK, TGF-␤ (TGF-␤ 1 ) and NF-B constitutes a potent prohypertrophic/remodeling axis. [2][3][4][5] The pathophysiological role of aldosterone in cardiac damage is evident in deoxycorticosterone acetate-salt (DOCA-salt) hypertension, 6 where elevated superoxide quenches NO to form peroxynitrite and 8-isoprostane, with subsequent stimulation of endothelin-1 to potentiate oxidative injury. 7,8 Moreov...

show abstract

“…19 -21 If, as suggested in the present study, CO serves as a counterbalancing influence to the sensitizing action of 20-HETE on responsiveness to constrictor stimuli, conditions in which vascular CO generation is compromised may also feature reduction of renal blood flow because of amplification of 20-HETE-induced sensitization of the renal vasculature to prevailing constrictor mechanisms. Such may be the case of young spontaneously hypertensive rats, animals which were shown to display diminished vascular HO activity 22 and greatly increased responsiveness to the sensitizing action of 20-HETE on phenylephrine-induced constriction of small arterial vessels. 4,23 The HO-CO and CYP4A-20-HETE systems also may be functionally coupled in relation to their regulatory functions in extrarenal circulatory beds.…”

Section: Perspectivesmentioning

confidence: 99%

Vascular CO Counterbalances the Sensitizing Influence of 20-HETE on Agonist-Induced Vasoconstriction

et al. 2004

View full text Add to dashboard Cite

Abstract-We examined the influence of interactions between Key Words: adrenergic receptor agonists Ⅲ vasopressins Ⅲ potassium channels Ⅲ renal circulation R ecent studies indicate that CO and 20-hydroxyeicosatetraenoic acid (20-HETE) of vascular origin influence the reactivity of rat arterial vessels to constrictor agonists in divergent directions. 1,2 CO, a product of heme metabolism by heme oxygenase (HO) isoforms Ϫ1 and Ϫ2, 3 reduces the sensitivity of vascular smooth muscle to phenylephrine and vasopressin. 1 In contrast, 20-HETE, a product of arachidonic acid -hydroxylation by isoforms of the cytochrome P450 4A family (CYP4A), 4,5 increases the sensitivity of vascular smooth muscle to phenylephrine 2 and vasopressin. 4 The reciprocal modulatory actions of CO and 20-HETE on vascular reactivity to phenylephrine are linked, respectively, to stimulation and inhibition of large conductance calcium-activated potassium (K Ca ) channels in vascular smooth muscle. 1,[5][6][7][8] In view of the aforementioned observations, it is conceivable that the sensitivity of arterial vessels to constrictor agonists is determined, at least in part, by the interplay between CO and 20-HETE manufactured by the vessels. One possibility is that the modulatory interplay simply results from the balance between regulatory substances with opposite actions on vascular reactivity. Another possibility is that the inhibitory action of CO on vasomotor responsiveness to phenylephrine relies on interference with the vascular production of 20-HETE. The latter possibility is supported by reports that CO inhibits many cytochrome P450 enzymes, including the CYP4A isoforms that catalyze 20-HETE synthesis. 5,9 This study was undertaken to test the hypothesis that an interplay between CO and 20-HETE of vascular origin influences the reactivity of renal vascular smooth muscle to phenylephrine and vasopressin. We examined whether vascular CO influences the production of vascular 20-HETE. We also examined whether the ability of CO and HO inhibitors to decrease and increase, respectively, the sensitivity of rat renal interlobar arteries to phenylephrine and vasopressin is influenced by the status of 20-HETE synthesis or the level of exogenous 20-HETE. were synthesized by J.R. Methods Chemicals and Solutions

show abstract

Induction of heme oxygenase-1 and stimulation of cGMP production by hemin in aortic tissues from hypertensive rats

Cited by 84 publications

References 51 publications

Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes

Upregulation of the heme oxygenase system ameliorates postprandial and fasting hyperglycemia in type 2 diabetes

Interaction Among Heme Oxygenase, Nuclear Factor-κB, and Transcription Activating Factors in Cardiac Hypertrophy in Hypertension

Vascular CO Counterbalances the Sensitizing Influence of 20-HETE on Agonist-Induced Vasoconstriction

Contact Info

Product

Resources

About