Peroxisome proliferator-activated receptor-γ ligands regulate endothelial membrane superoxide production

Hwang, Jae Ryoung; Kleinhenz, Dean J.; Lassègue, Bernard; Griendling, Kathy K.; Dikalov, Sergey; Hart, C. Michael

doi:10.1152/ajpcell.00474.2004

Cited by 245 publications

(185 citation statements)

References 37 publications

Supporting

Mentioning

163

Contrasting

Unclassified

Order By: Relevance

“…In the mouse, in contrast to the rat, Pio caused a small, yet significant, increase in eNOS phosphorylation at both Ser633 and Ser1177, suggesting the activation by protein kinase A (and/or other kinases) (26). Other studies have suggested that PPAR␥ agonists increase NO production by eNOS without affecting the total eNOS expression (10,28,47). Hwang et al (28) reported that ciglitazone increases the bioavailability of NO by an increased expression of Cu/Zn-superoxide dismutase and a suppression of NADPH oxidase.…”

Section: Role Of Enosmentioning

confidence: 97%

“…Other studies have suggested that PPAR␥ agonists increase NO production by eNOS without affecting the total eNOS expression (10,28,47). Hwang et al (28) reported that ciglitazone increases the bioavailability of NO by an increased expression of Cu/Zn-superoxide dismutase and a suppression of NADPH oxidase. On the other hand, Cho et al (12) reported that a prolonged treatment with troglitazone increased calcium-dependent NOS activity in bovine aortic endothelial cells by augmenting eNOS phosphorylation at Ser1179 without a detectable change in the total eNOS levels.…”

Section: Role Of Enosmentioning

confidence: 99%

See 1 more Smart Citation

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

Ye¹,

Lin²,

Manickavasagam³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Ye Y, Lin Y, Manickavasagam S, Perez-Polo JR, Tieu BC, Birnbaum Y. Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice. Am J Physiol Heart Circ Physiol 295: H2436 -H2446, 2008. First published October 17, 2008 doi:10.1152/ajpheart.00690.2008.-Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-␥ agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA 2 and COX2, and increases myocardial 6-keto-PGF1␣ levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice. Male C57BL/6 wild-type (WT), eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ mice received 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 Pio (Pioϩ) or water alone (PioϪ) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4 Ϯ 1.4% vs. 39.0 Ϯ 1.1%; P Ͻ 0.001), as well as in the eNOS Ϫ/Ϫ (32.0 Ϯ 1.6% vs. 44.2 Ϯ 1.9%; P Ͻ 0.001) and iNOS Ϫ/Ϫ (18.0 Ϯ 1.2% vs. 45.5 Ϯ 2.3%; P Ͻ 0.001) mice. The protective effect of Pio in eNOS Ϫ/Ϫ mice was smaller than in the WT (P Ͻ 0.001) and iNOS Ϫ/Ϫ (P Ͻ 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS Ϫ/Ϫ mice. iNOS was undetectable in all six groups. Pio increased cPLA 2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ , mice. Pio increased the myocardial 6-keto-PGF 1␣ levels and cPLA2 and COX2 activity in the WT, eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized. endothelial nitric oxide synthase; inducible nitric oxide synthase; peroxisome proliferator-activated receptor-␥ PROTECTION AGAINST ischemia-reperfusion injury may have a potential benefit in three distinct clinical situations: 1) limiting reperfusion injury in patients presenting with ST-elevation acute myocardial infarction before undergoing reperfusion therapy; 2) short-to intermediate-term treatment before elective procedures that may pose a risk for myocardial ischemia, such as cardiac or noncardiac surgery or percutaneous coronary interventions; and 3) long-term treatment in patients with established coronary artery disease to minimize the damage from an effort-induced ischemia or a potential future myocardial infarction. In the present study we studied whether the myocardial protection effects of intermediate-term pretreatment with pioglitazone (Pio) is dependent on nitric oxide (NO) synthases (NOSs), using a model that may be relevant to the second option mentioned above....

show abstract

Section: Role Of Enosmentioning

confidence: 97%

Section: Role Of Enosmentioning

confidence: 99%

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

Ye¹,

Lin²,

Manickavasagam³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

show abstract

“…The catalase and SOD gene promoters contain the PPRE, indicating that they are directly regulated by 111). It is known that transient cerebral ischemia causes a marked increase in the production of ROS, while at the same time, reducing hippocampal levels of glutathione (GSH), an important ROS scavenger (8).…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

378

246

View full text Add to dashboard Cite

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ 2 ) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZDinduced neuroprotection in various animal models of CNS injury with an emphasis on stroke. KeywordsTranscription Factor; Inflammation; Brain Damage; Nuclear Factor; Cerebral Ischemia; Stroke; Neuroprotection; Review INTRODUCTIONStroke is the leading cause of long-term disability in the adult population worldwide. A variety of pathophysiological processes contribute to the irreversible neuronal injury that eventually results in neurological dysfunction after stroke. The complex nature of these processes involves specific cell types that effect several downstream signalling pathways. In a majority of stroke patients, only a small area of the brain tissue, the ischemic core, is irreversibly damaged. A much larger volume of the brain tissue surrounding the ischemic core, called the penumbra, can potentially recover if treatment is provided in a timely manner (3). Tissue protection and regeneration are tightly regulated by cell growth, survival and cell death signals provided by the cellular microenvironment. Hence, understanding the molecular mechanisms that govern Send correspondence to: Dr. Raghu Vemuganti, Department of Neurological Surgery, K4/8 Mail code CSC 8660, 600 Highland Avenue, Madison, WI 53792, Tel:608-263-4055, Fax:608-263-1728, E-mail: vemugant@neurosurg.wisc.edu. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2009 August 28. Published in final edited form as:Fr...

show abstract

“…To judge from several reports that have appeared in recent years, PPARγ agonists may improve endothelium-dependent relaxation in animals and patients with any of a number of cardiovascular diseases via reduced oxidative stress (Bagi et al, 2004;Caballero et al, 2003;De Ciuceis et al, 2007;Howarth et al, 2006;Maegawa et al, 2007;Matsumoto et al, 2007d;Namikoshi et al, 2007;Ryan et al, 2004;Stakos et al, 2003). Further, it has been found that in ECs in culture, activation of PPARγ enhances the expression of Cu/Zn-SOD , and also that PPARγ agonists stimulate the activity and protein expression of Cu/Zn-SOD in ECs (Hwang et al, 2005) (Fig. 1).…”

Section: Pparγ Agonists and Oxidative Stress In Ecsmentioning

confidence: 99%

“…For example, activation of PPARγ was found (a) to decrease both the mRNA for NAD(P)H oxidase subunit p22phox and the p47phox protein level in human aortic ECs , (b) to reduce the protein expression of p22phox and Rac1 in the aorta (Nakamura et al, 2008;Namikoshi et al, 2007), and (c) to suppress Nox homolog expression in both vascular ECs in vitro and in the diabetic mouse aorta (Hwang et al, 2005(Hwang et al, , 2007.…”

Section: Pparγ Agonists and Oxidative Stress In Ecsmentioning

confidence: 99%

Relationships among ET-1, PPAR.GAMMA., oxidative stress and endothelial dysfunction in diabetic animals

Matsumoto

Kobayashi

Kamata

2008

J. Smooth Muscle Res.

View full text Add to dashboard Cite

Macro-and microvascular disorders currently represent the principal causes of morbidity and mortality in patients with diseases involving the cardiovascular system, such as atherosclerosis, hypertension, stroke, and diabetes. Abnormal vasomotor responses and impaired endothelium-dependent vasodilation have been demonstrated in a number of vessels in a variety of animal models and in humans with such diseases. Endothelial dysfunction plays a key role in the development of these diseases, yet the genesis of this endothelial dysfunction and its associated vasomotor abnormalities remain poorly understood. Peroxisome proliferator-activated receptor (PPAR)γ is a nuclear receptor and transcription factor in the steroid superfamily, and PPARγ agonists (the thiazolidinediones) are used clinically to treat type 2 diabetes. Recent studies have revealed that as well as being involved in adipogenesis and in increased sensitivity to insulin, PPARγ plays critical roles in the vasculature. In the present review, we discuss the beneficial effects of PPARγ agonists on vasomotor activities, focusing in particular on endothelium-dependent relaxation in vessels affected by cardiovascular diseases.

show abstract

Peroxisome proliferator-activated receptor-γ ligands regulate endothelial membrane superoxide production

Cited by 245 publications

References 37 publications

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Relationships among ET-1, PPAR.GAMMA., oxidative stress and endothelial dysfunction in diabetic animals

Contact Info

Product

Resources

About