New Therapeutic Targets in Cardiology

Martin, Eva Denise; Nicola, G.F. De; Marber, Michael

doi:10.1161/circulationaha.111.071886

Cited by 70 publications

(51 citation statements)

References 115 publications

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“…In line with these studies, we also show significantly augmented p38mapk activation in the mouse aortas of HFD-induced obesity (Figure 1). Activation of p38mapk involves multiple mechanisms which are not fully understood, yet [14]. Hyperglycemia has been implicated in activation of p38mapk in various types of cells including endothelial cells, cardiomyoblasts, and dendritic cells [35][36][37].…”

Section: Discussionmentioning

confidence: 99%

“…Evidence has been presented that p38mapk is an important signaling pathway sensing cellular stress and is involved in pathogenesis of cardiovascular diseases and eNOS-uncoupling [14,15]. Mammalian p38mapk has four isoforms, α, β, δ, γ, which are expressed to different extent in specific cells and tissues, and function as sensors to various stressors, including oxidative stress, inflammatory stimuli, oncogenes [14,16].…”

Section: Introductionmentioning

confidence: 99%

“…Mammalian p38mapk has four isoforms, α, β, δ, γ, which are expressed to different extent in specific cells and tissues, and function as sensors to various stressors, including oxidative stress, inflammatory stimuli, oncogenes [14,16]. Of the four enzyme isoforms, p38α is the best recognized isoenzyme of cardiovascular importance [14].…”

Section: Introductionmentioning

confidence: 99%

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p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity

Rajapakse

Montani

et al. 2014

Cardiovasc Diabetol

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Background: Endothelial nitric oxide synthase (eNOS)-uncoupling links obesity-associated insulin resistance and type-II diabetes to the increased incidence of cardiovascular disease. Studies have indicated that increased arginase is involved in eNOS-uncoupling through competing with the substrate L-arginine. Given that arginase-II (Arg-II) exerts some of its biological functions through crosstalk with signal transduction pathways, and that p38 mitogen-activated protein kinase (p38mapk) is involved in eNOS-uncoupling, we investigated here whether p38mapk is involved in Arg-II-mediated eNOS-uncoupling in a high fat diet (HFD)-induced obesity mouse model. Methods: Obesity was induced in wild type (WT) and Arg-II-deficient (Arg-II

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity

Rajapakse

Montani

et al. 2014

Cardiovasc Diabetol

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“…Many MAPK interacting proteins have a conserved kinase interaction motif (KIM) or docking motif (D motif) with the consensus sequence of (R/K) 1 to 2 -(X) 2-6 -Φ A -X-Φ B , where Φ A and Φ B represent the hydrophobic residues [15]. Zhou et al [27] previously showed that TAB1 also contains a KIM sequence (residues 395414) that plays a major role in high-affinity p38α binding.…”

Section: Overall Structure Of P38α-peptab1 Complexmentioning

confidence: 99%

“…Ge et al [5] later found that TAB1 can interact with p38α but no other p38 family members, and the interaction of TAB1 with p38α leads to dual autophosphorylation of p38α on both Thr and Tyr sites, in vitro and in vivo. The TAB1-dependent p38α activation appears to play important roles in some physiological and pathological processes, such as injury during myocardial ischemia, maturation of monocyte-derived dendritic cells, maintenance of peripheral T-cell anergy, and intracellular infection of parasite induced interleukin-12 production [1, [14][15][16][17]. On the other hand, Cheung et al [18] suggested that the activated p38α can phosphorylate TAB1, which feedback controlled the activation of TAK1 and reduced the sequential activation of MKK3/6 and p38α.…”

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confidence: 99%

Crystal structure of the p38α MAP kinase in complex with a docking peptide from TAB1

Xin

2013

Sci. China Life Sci.

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The mitogen-activated protein kinase (MAPK) p38α is a key regulator in many cellular processes, whose activity is tightly regulated by upstream kinases, phosphatases and other regulators. Transforming growth factor-β activated kinase 1 (TAK1) is an upstream kinase in p38α signaling, and its full activation requires a specific activator, the TAK1-binding protein (TAB1). TAB1 was also shown to be an inducer of p38α's autophosphorylation and/or a substrate driving the feedback control of p38α signaling. Here we determined the complex structure of the unphosphorylated p38α and a docking peptide of TAB1, which shows that the TAB1 peptide binds to the classical MAPK docking groove and induces long-range conformational changes on p38α. Our structural and biochemical analyses suggest that TAB1 is a reasonable substrate of p38α, yet the interaction between the docking peptide and p38α may not be sufficient to trigger trans-autophosphorylation of p38α. p38α MAP kinase, TAB1, KIM, crystal structure Citation:Xin F J, Wu J W. Crystal structure of the p38α MAP kinase in complex with a docking peptide from TAB1.

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Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction

O’Donoghue

Glaser

Cavender

et al. 2016

JAMA

209

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IMPORTANCE p38 Mitogen-activated protein kinase (MAPK)-stimulated inflammation is implicated in atherogenesis, plaque destabilization, and maladaptive processes in myocardial infarction (MI). Pilot data in a phase 2 trial in non-ST elevation MI indicated that the p38 MAPK inhibitor losmapimod attenuates inflammation and may improve outcomes. OBJECTIVE To evaluate the efficacy and safety of losmapimod on cardiovascular outcomes in patients hospitalized with an acute myocardial infarction. DESIGN, SETTING, AND PATIENTS LATITUDE-TIMI 60, a randomized, placebo-controlled, double-blind, parallel-group trial conducted at 322 sites in 34 countries from June 3, 2014, until December 8, 2015. Part A consisted of a leading cohort (n = 3503) to provide an initial assessment of safety and exploratory efficacy before considering progression to part B (approximately 22 000 patients). Patients were considered potentially eligible for enrollment if they had been hospitalized with an acute MI and had at least 1 additional predictor of cardiovascular risk. INTERVENTIONS Patients were randomized to either twice-daily losmapimod (7.5 mg; n = 1738) or matching placebo (n = 1765) on a background of guideline-recommended therapy. Patients were treated for 12 weeks and followed up for an additional 12 weeks. MAIN OUTCOMES AND MEASURES The primary end point was the composite of cardiovascular death, MI, or severe recurrent ischemia requiring urgent coronary revascularization with the principal analysis specified at week 12. RESULTS In part A, among the 3503 patients randomized (median age, 66 years; 1036 [29.6%] were women), 99.1% had complete ascertainment for the primary outcome. The primary end point occurred by 12 weeks in 123 patients treated with placebo (7.0%) and 139 patients treated with losmapimod (8.1%; hazard ratio, 1.16; 95% CI, 0.91-1.47; P = .24). The on-treatment rates of serious adverse events were 16.0% with losmapimod and 14.2% with placebo. CONCLUSIONS AND RELEVANCE Among patients with acute MI, use of losmapimod compared with placebo did not reduce the risk of major ischemic cardiovascular events. The results of this exploratory efficacy study did not justify proceeding to a larger efficacy trial in the existing patient population.

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New Therapeutic Targets in Cardiology

Cited by 70 publications

References 115 publications

p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity

p38 mitogen-activated protein kinase is involved in arginase-II-mediated eNOS-Uncoupling in Obesity

Crystal structure of the p38α MAP kinase in complex with a docking peptide from TAB1

Effect of Losmapimod on Cardiovascular Outcomes in Patients Hospitalized With Acute Myocardial Infarction

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