Mode of Inhibitory Action of Bilirubin on Protein Kinase C

Sano, Kimihiko; Nakamura, Hajime; Matsuo, Tamotsu

doi:10.1203/00006450-198506000-00017

Cited by 87 publications

(41 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The HO-1 product, bilirubin, has been shown to inhibit protein kinase C and NADPH oxidase activities (46). Recently, up-regulation of HO-1 gene expression was shown to decrease the availability of the heme-containing gp91 subunit necessary for NADPH oxidase activity and O 2 Ϫ ) generation and to increase bilirubin formation (7).…”

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Enhances Renal Mitochondrial Transport Carriers and Cytochrome c Oxidase Activity in Experimental Diabetes

Noia

Driesche

Palmieri

et al. 2006

Journal of Biological Chemistry

109

105

View full text Add to dashboard Cite

Up-regulation of heme oxygenase (HO-1) by either cobalt protoporphyrin (CoPP) or human gene transfer improves vascular and renal function by several mechanisms, including increases in antioxidant levels and decreases in reactive oxygen species (ROS) in vascular and renal tissue. The purpose of the present study was to determine the effect of HO-1 overexpression on mitochondrial transporters, cytochrome c oxidase, and anti-apoptotic proteins in diabetic rats (streptozotocin, (STZ)-induced type 1 diabetes). Renal mitochondrial carnitine, deoxynucleotide, and ADP/ATP carriers were significantly reduced in diabetic compared with nondiabetic rats ( p < 0.05). The citrate carrier was not significantly decreased in diabetic tissue. CoPP administration produced a robust increase in carnitine, citrate, deoxynucleotide, dicarboxylate, and ADP/ATP carriers and no significant change in oxoglutarate and aspartate/ glutamate carriers. The increase in mitochondrial carriers (MCs) was associated with a significant increase in cytochrome c oxidase activity. The administration of tin mesoporphyrin (SnMP), an inhibitor of HO-1 activity, prevented the restoration of MCs in diabetic rats. Human HO-1 cDNA transfer into diabetic rats increased both HO-1 protein and activity, and restored mitochondrial ADP/ ATP and deoxynucleotide carriers. The increase in HO-1 by CoPP administration was associated with a significant increase in the phosphorylation of AKT and levels of BcL-XL proteins. These observations in experimental diabetes suggest that the cytoprotective mechanism of HO-1 against oxidative stress involves an increase in the levels of MCs and anti-apoptotic proteins as well as in cytochrome c oxidase activity.The heme-heme oxygenase (HO), 4 HO-1 and HO-2, isoforms, are viewed as having a major role in the formation of carbon monoxide (CO) and bilirubin, and in heme breakdown (1-3). The fact that HO-1 is strongly induced by its substrate, heme, and by oxidant stress, in conjunction with the robust ability of HO-1 to guard against oxidative insult (4, 5), suggests a countervailing system to oxidative stress injury. HO-1 is a regulator of endothelial cell integrity and oxidative stress (4 -6). Up-regulation of HO-1 by pharmacological agents, including cobalt protoporphyrin (CoPP), has been shown to increase superoxide dismutase and to decrease reactive oxygen species (ROS) and NAD(P)H oxidase activity in vitro and in vivo (7-9). In earlier studies, we, as well as others, have demonstrated that overexpression of the HO-1 gene in human, rabbit, and rat endothelial cells not only renders the cells resistant to agents that elicit oxidative stress but also enhances cell growth (6) and angiogenesis (10, 11) via HO-1-derived CO (12). More recently, up-regulation of HO-1 has been shown to prevent endothelial cell death and sloughing in diabetic rats (8).Mitochondrially generated ROS have been well documented in diabetes (13,14). Hyperglycemia-mediated local formation of ROS is considered to be a major contributing factor to renal and vascula...

show abstract

Section: Discussionmentioning

confidence: 99%

Heme Oxygenase-1 Enhances Renal Mitochondrial Transport Carriers and Cytochrome c Oxidase Activity in Experimental Diabetes

Noia

Driesche

Palmieri

et al. 2006

Journal of Biological Chemistry

109

105

View full text Add to dashboard Cite

show abstract

“…Bilirubin may have vascular protective effects as well. A higher serum bilirubin level is related to a decrease in lipid peroxidation and is associated with a decrease in the risk for coronary artery disease in humans (Sano et al, 1985;Vasa et al, 2001).…”

Section: F Heme Oxygenase-1 In Myocardial Ischemiareperfusion Injurymentioning

confidence: 99%

“…Bilirubin inhibits NADPH oxidase (Kwak et al, 1991) and PKC activity (Sano et al, 1985). Both enzymes have been shown to mediate angiotensin II-induced vascular injury (Rajagopalan et al, 1996;Ishizaka et al, 2000).…”

Section: Role Of Bilirubin/biliverdinmentioning

confidence: 99%

Pharmacological and Clinical Aspects of Heme Oxygenase

Abraham

Kappas²

2008

Pharmacol Rev

1,012

988

View full text Add to dashboard Cite

“…HO-2-derived CO from renal small arteries regulates 105 psK channels and modulates vascular reactivity in response to vasoconstrictors (13,14). Bilirubin has been shown to inhibit NADPH oxidase (15) and protein kinase C activities (16,17).…”

mentioning

confidence: 99%

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Goodman¹,

Chander²,

Rezzani³

et al. 2006

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Heme oxygenase-1 (HO-1) and -2 play an important role in cytoprotection and are physiologic regulators of heme-dependent protein synthesis in renal tissues. The impact of HO-2 deletion comparing hyperglycemic HO-2 (؉/؉) mice and HO-2 knockout (؊/؊) mice was examined. Hyperglycemia was induced by streptozotocin (STZ) injection, and its effect on renal HO-1/HO-2 protein, HO activity, and creatinine levels were assessed. The effect of HO induction using systemic administration of the HO inducers heme or cobalt protoporphyrin and the effect of HO inhibition using systemic administration of the HO inhibitor tin mesoporphyrin also were assessed in STZ-treated mice. In STZ-treated HO-2 (؊/؊) mice, there was marked renal functional impairment as reflected by an increase in plasma creatinine, associated with acute tubular damage and microvascular pathology as compared with HO-2 (؉/؉). In these animals, HO activity was decreased with a concomitant increase in superoxide anion. Upregulation of HO-1 in HO-2 (؊/؊) mice by weekly administration of cobalt protoporphyrin prevented the increase in plasma creatinine levels and tubulointerstitial and microvascular pathology. Inhibition of HO activity by administration of tin mesoporphyrin accentuated superoxide production and increased creatinine levels in hyperglycemic HO-2 (؊/؊) mice. In conclusion, HO-2 deficiency enhanced STZ-induced renal dysfunction and morphologic injury and HO-1 upregulation in HO-2 (؊/؊) mouse rescue and prevented the morphologic damage. These observations indicate that HO activity is essential in preserving renal function and morphology in STZ-induced diabetic mice probably via mitigation of concomitant oxidative stress.

show abstract

Mode of Inhibitory Action of Bilirubin on Protein Kinase C

Cited by 87 publications

References 7 publications

Heme Oxygenase-1 Enhances Renal Mitochondrial Transport Carriers and Cytochrome c Oxidase Activity in Experimental Diabetes

Heme Oxygenase-1 Enhances Renal Mitochondrial Transport Carriers and Cytochrome c Oxidase Activity in Experimental Diabetes

Pharmacological and Clinical Aspects of Heme Oxygenase

Heme Oxygenase-2 Deficiency Contributes to Diabetes-Mediated Increase in Superoxide Anion and Renal Dysfunction

Contact Info

Product

Resources

About