Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection

Olzinski, Alan R.; McCafferty, Tara A; Zhao, Shufang; Behm, David J.; Eybye, Marianne; Maniscalco, Kristeen; Bentley, Ross; Frazier, Kendall S.; Milliner, Chavon M; Mirabile, Rosanna C.; Coatney, Robert W.; Willette, Robert N.

doi:10.1016/j.cardiores.2004.12.021

Cited by 41 publications

(35 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…21 p38 inhibition prevents failure-induced cardiac damage caused by fibrosis and apoptosis, [21][22][23] and also tissue damage in other organs. 24,25 Similar results are obtained by genetic ablation of the p38 route (reviewed in ref. 17) while genetic activation in mice of the p38 pathway causes elevated cardiac dysfunction 26 and early death.…”

Section: The P38 Modulesupporting

confidence: 78%

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

Mayor¹,

Jurado-Pueyo²,

Campos³

et al. 2007

Cell Cycle

View full text Add to dashboard Cite

Section: The P38 Modulesupporting

confidence: 78%

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

Mayor¹,

Jurado-Pueyo²,

Campos³

et al. 2007

Cell Cycle

View full text Add to dashboard Cite

“…In SHRs, NOS inhibition causes end organ damage that could be blocked by p38 MAP kinase inhibition. 30 We demonstrated in this study that NOS inhibition can increase ROS formation in cardiomyocytes from SHRs. In salt-sensitive rats, eNOS expression decreased when the animals were fed with an 8% NaCl diet for 5 weeks.…”

Section: Discussionmentioning

confidence: 49%

Lack of Endothelial Nitric Oxide Synthase–Derived Nitric Oxide Formation Favors Hypertrophy in Adult Ventricular Cardiomyocytes

et al. 2007

View full text Add to dashboard Cite

Abstract-Reduced activity and expression of endothelial NO synthase (eNOS) is observed in cardiomyocytes from pressure-overloaded hearts with heart failure. The present study was aimed to investigate whether reduced eNOSderived NO production contributes to the hypertrophic growth and phenotype of these cardiomyocytes. Cultured ventricular cardiomyocytes from adult rats were exposed to N-nitro-L-arginine (L-NNA) to inhibit global NO formation, and cultured cardiomyocytes derived from eNOS-deficient mice were used as a model of genetic knockout of eNOS. Cell growth, formation of oxygen-derived radicals (reactive oxygen species [ROS]), activation of p38 mitogen-activated protein (MAP) kinase phosphorylation, and cytokine expression in cardiomyocytes were investigated. L-NNA caused a concentration-dependent acceleration of the rate of protein synthesis and an increase in cell size. This effect was sensitive to p38 MAP kinase inhibition or antioxidants. L-NNA induced a rapid increase in ROS formation, subsequent activation of p38 MAP kinase, and p38 MAP kinase-dependent increases in the expression of transforming growth factor-␤ and tumor necrosis factor-␣. Similar changes (increased ROS formation, p38 MAP kinase phosphorylation, and cytokine induction) were also observed in cardiomyocytes derived from eNOSϩ/ϩ mice when exposed to L-NNA. Cardiomyocytes from eNOSϪ/Ϫ mice displayed higher p38 MAP kinase phosphorylation and cytokine expression under basal conditions, but neither these 2 parameters nor ROS formation were increased in the presence of L-NNA. In conclusion, our data support the hypothesis that reduced eNOS activity in cardiomyocytes contributes to the onset of myocardial hypertrophy and increased cytokine expression, which are involved in the transition to heart failure. encoded by the NOS-3 gene). eNOS-deficient mice develop a hypertensive phenotype and moderate cardiac hypertrophy. 1 eNOS is also expressed in nonendothelial cells in concert with other NOS isoforms. In adult ventricular cardiomyocytes, eNOS and the neuronal NOS (nNOS encoded by the NOS-1 gene) are constitutively expressed. eNOS is located at the sarcolemmal and T-tubular caveolae where it is associated with caveolin-3. The activity of eNOS modifies ␤-adrenoceptor signaling. 2,3 nNOS seems to be localized at the sarcoplasmic reticulum, where it interferes with the activity of calcium-handling proteins. 4 Interestingly, eNOS undergoes downregulation in cardiomyocytes under conditions of hypertrophic cardiomyopathy and heart failure, but nNOS undergoes upregulation. [5][6][7] Under experimental conditions, inhibition of endogenous NO formation induces myocardial hypertrophy, but this is independent of its hypertensive effect. 8 The underlying mechanisms by which reduced NO formation contributes to myocardial hypertrophy are unknown. In the present study we hypothesized that an inhibition of eNOS-derived NO disturbs the balance between NO and NAD(P)H oxidase-generated reactive oxygen species (ROS). As a possible signal transduction pathway, we...

show abstract

“…In rodent models of end organ dysfunction, p38 MAPK inhibitors have been shown to be extremely effective in eliciting a survival benefit in part via promoting endothelial protection. 20,22,23 However in the present study, the deaths in the Ang II infused apoE Ϫ/Ϫ mice were most likely attributable to aneurysm rupture initiated by matrix metalloproteinase (MMP)/chymase activation. 21,24,25 Ang II has been shown to activate the p38 MAPK signaling pathway in a number of vascular cell types 18,19,26 including macrophages, 27 and is an important signaling pathway for the recruitment of leukocytes.…”

Section: Discussionmentioning

confidence: 58%

p38 MAPK Inhibition Reduces Aortic Ultrasmall Superparamagnetic Iron Oxide Uptake in a Mouse Model of Atherosclerosis

Morris

Olzinski

Bernard

et al. 2008

ATVB

View full text Add to dashboard Cite

Objective-Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation. The purpose of this study was to noninvasively evaluate USPIO uptake in aorta of apoE Ϫ/Ϫ mice and to determine the effects of Angiotensin II (Ang II) infusion and chronic antiinflammatory treatment with a p38 MAPK inhibitor on this uptake. Methods and Results-ApoEϪ/Ϫ mice were administered saline or Ang II (1.44 mg/kg/d) for 21 days. In vivo MRI assessment of USPIO uptake in the aortic arch was observed in all animals. However, although the Ang II group had significantly higher absolute iron content (1103%, PϽ0.001) in the aortic arch compared with the saline group, the p38 MAPK inhibitor (SB-239063, 150 mg/kg/d) treatment group did not (16%, NS). The in vivo MRI signal intensity was significantly correlated to the absolute iron content in the aortic arch. Histological evaluation of the aortic root lesion area showed colocalization of USPIO with macrophages and a reduction in USPIO but not macrophage content with SB-239063 treatment. Conclusion-The present study demonstrates that noninvasive assessment of USPIO uptake, as a marker for inflammation in murine atherosclerotic plaque, is feasible and that p38 MAPK inhibition attenuates the uptake of USPIO in aorta of Ang II-infused apoE Key Words: atherosclerosis Ⅲ inflammation Ⅲ magnetic resonance imaging Ⅲ USPIO Ⅲ apoE Ϫ/Ϫ Ⅲ p38 MAPK A lthough experimental evidence linking inflammatory processes to the fate of the atherosclerotic plaque development exists, it is difficult to examine these processes noninvasively and to provide convincing links between preclinical and clinical studies. In this regard, ultrasmall superparamagnetic iron oxide (USPIO) contrast agents, optimized for uptake by the mononuclear phagocytic system, 1-3 are of particular interest for translational cardiovascular research. These agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation in humans 4 -6 as well as hypercholesterolemic balloon-injured NZW 7 and WHHL 8 -11 rabbits. However, descriptions of USPIO use in extensively-studied murine genetic models of atherosclerosis have been limited. Investigators have used other targeted 12,13 and nontargeted 14 approaches to noninvasively assess plaque burden or inflammation in atherosclerotic mouse models. Additionally, superparamagnetic iron oxide (SPIO) has been used to quantify monocyte recruitment histologically in atherosclerotic lesions of the apolipoprotein E-deficient (apoE Ϫ/Ϫ ) mouse. 15 In that study, acute administration of tumor necrosis factor (TNF), interleukin (IL)-1␤, and interferon (INF)-␥ was shown to stimulate SPIO uptake by 4-fold in plaque. Although this study supports the hypothesis that plaque targeting of the USPIO contrast agent in mouse is facilitated by monocyte recruitment or activation of macrophage phagocytosis, noninvasive assessment of USPIO uptake in mouse atherosclerotic lesions has not been reported. Recent evidence sugg...

show abstract

Hypertensive target organ damage is attenuated by a p38 MAPK inhibitor: role of systemic blood pressure and endothelial protection

Cited by 41 publications

References 24 publications

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

Interfering with MAP Kinase Docking Interactions: Implications and Perspectives for the p38 Route

Lack of Endothelial Nitric Oxide Synthase–Derived Nitric Oxide Formation Favors Hypertrophy in Adult Ventricular Cardiomyocytes

p38 MAPK Inhibition Reduces Aortic Ultrasmall Superparamagnetic Iron Oxide Uptake in a Mouse Model of Atherosclerosis

Contact Info

Product

Resources

About