Development of a Practical Synthesis of Naphthyridone p38 MAP Kinase Inhibitor MK-0913

Stress is gaining increasing acceptance as an independent risk factor contributing to adverse cardiovascular outcomes. Potential mechanisms responsible for the deleterious effects of stress on the development and progression of cardiovascular disease remain to be elucidated. An established animal model of stress in humans is the prenatally stressed (PS) rat. We stressed rats in their third trimester of pregnancy by daily injections of saline and moving from cage to cage. Male offspring of these stressed dams (PS) and age-matched male control offspring (control) were further subjected to restraint stress (R) at 6 and 7 wk of age. Echocardiography revealed a significant decrease in fractional shortening in PS + R vs. controls + R (45.8 ± 3.9 vs. 61.9 ± 2.4%, PS + R vs. controls + R; P < 0.01; n = 12). Isolated adult rat ventricular myocytes from PS + R also revealed diminished fractional shortening (6.7 ± 0.8 vs. 12.7 ± 1.1%, PS + R vs. controls + R; P < 0.01; n = 24) and blunted inotropic responses to isoproterenol ( P < 0.01; n = 24) determined by automated border detection. The p38 mitogen-activated protein (MAP) kinase inhibitor SB-203580 blocked p38 MAP kinase phosphorylation, reversed the depression in fractional shortening, and partially ameliorated the blunted adrenergic signaling seen in adult rat ventricular myocytes from PS + R. Phosphorylation of p38 MAP kinase in cardiac myocytes by stress may be sufficient to lead to myocardial dysfunction in animal models and possibly humans.

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Stimulation of cardiac fibroblast Piezo1 channels opposes myofibroblast differentiation and induces IL-6 secretion via Ca2+-mediated p38 MAP kinase activation

10.1101/603456 ◽

2019 ◽

Cited By ~ 1

Author(s):

Nicola M. Blythe ◽

Vasili Stylianidis ◽

Melanie J. Ludlow ◽

Hamish T. J. Gilbert ◽

Elizabeth L. Evans ◽

...

Keyword(s):

Map Kinase ◽

Structural Integrity ◽

Kinase Inhibitor ◽

Cardiac Fibroblasts ◽

Collagen Gel ◽

Mechanical Stretch ◽

Cardiac Fibroblast ◽

Ruthenium Red ◽

P38 Map Kinase ◽

Dependent Manner

AbstractPiezo1 is a mechanosensitive cation channel with widespread physiological importance; however its role in the heart is poorly understood. Cardiac fibroblasts are responsible for preserving the structural integrity of the myocardium and play a key role in regulating its repair and remodeling following stress or injury. We investigated expression and function of Piezo1 in cultured human and mouse cardiac fibroblasts. RT-PCR studies confirmed expression ofPiezo1mRNA in cardiac fibroblasts at similar levels to endothelial cells. Fura-2 intracellular Ca2+measurements validated Piezo1 as a functional ion channel that was activated by the Piezo1 agonist, Yoda1. Yoda1-induced Ca2+entry was inhibited by Piezo1 blockers (gadolinium, ruthenium red) and the Ca2+response was reduced proportionally by Piezo1 siRNA knockdown or in cells fromPiezo1+/−mice. Investigation of Yoda1 effects on selected remodeling genes indicated that Piezo1 activation opposed cardiac fibroblast differentiation; data confirmed by functional collagen gel contraction assays. Piezo1 activation using Yoda1 or mechanical stretch also increased the expression of interleukin-6 (IL-6), a mechanosensitive pro-hypertrophic and pro-fibrotic cytokine, in a Piezo1-dependent manner. Multiplex kinase activity profiling combined with kinase inhibitor studies and phospho-specific western blotting, established that Piezo1 activation stimulated IL-6 secretion via a pathway involving p38 MAP kinase, downstream of Ca2+entry. In summary, this study reveals that cardiac fibroblasts express functional Piezo1 channels coupled to reduced myofibroblast activation and increased secretion of paracrine signaling molecules that can modulate cardiac remodeling.

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Coupling of M2 muscarinic receptors to ERK MAP kinases and caldesmon phosphorylation in colonic smooth muscle

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2000.278.3.g429 ◽

2000 ◽

Vol 278 (3) ◽

pp. G429-G437 ◽

Cited By ~ 21

Author(s):

Amy K. Cook ◽

Michael Carty ◽

Cherie A. Singer ◽

Ilia A. Yamboliev ◽

William T. Gerthoffer

Keyword(s):

Smooth Muscle ◽

Map Kinase ◽

Muscarinic Receptors ◽

Map Kinases ◽

Kinase Inhibitor ◽

Receptor Activation ◽

Inhibitory Effect ◽

Subsequent Treatment ◽

P38 Map Kinase

Coupling of M2 and M3 muscarinic receptors to activation of mitogen-activated protein (MAP) kinases and phosphorylation of caldesmon was studied in canine colonic smooth muscle strips in which M3 receptors were selectively inactivated by N, N-dimethyl-4-piperidinyl diphenylacetate (4-DAMP) mustard (40 nM). ACh elicited activation of extracellular signal-regulated kinase (ERK) 1, ERK2, and p38 MAP kinases in control muscles and increased phosphorylation of caldesmon (Ser789), a putative downstream target of MAP kinases. Alkylation of M3 receptors with 4-DAMP had only a modest inhibitory effect on ERK activation, p38 MAP kinase activation, and caldesmon phosphorylation. Subsequent treatment with 1 μM AF-DX 116 completely prevented activation of ERK and p38 MAP kinase and prevented caldesmon phosphorylation. Caldesmon phosphorylation was blocked by the MAP kinase/ERK kinase inhibitor PD-98509 but not by the p38 MAP kinase inhibitor SB-203580. These results indicate that colonic smooth muscle M2 receptors are coupled to ERK and p38 MAP kinases. Activation of ERK, but not p38 MAP kinases, results in phosphorylation of caldesmon in vivo, which is a novel function for M2receptor activation in smooth muscle.

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PD55-05 THERAPEUTIC EFFECTS OF P38 MAP KINASE INHIBITOR ON BLADDER DYSFUNCTION IN MICE WITH SPINAL CORD INJURY (SCI)

The Journal of Urology ◽

10.1016/j.juro.2018.02.2625 ◽

2018 ◽

Vol 199 (4S) ◽

Author(s):

Nobutaka Shimizu ◽

Takahisa Suzuki ◽

Ei-ichiro Takaoka ◽

Joombeom Kwon ◽

Naoki Wada ◽

...

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Map Kinase ◽

Bladder Dysfunction ◽

Kinase Inhibitor ◽

P38 Map Kinase ◽

Therapeutic Effects ◽

Cord Injury

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Development of a Practical Synthesis of Naphthyridone p38 MAP Kinase Inhibitor MK-0913

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Selective Regulation of T Cell IL-5 Synthesis by OM-01, JTE-711 and p38 MAP Kinase Inhibitor: Independent Control of Th2 Cytokines, IL-4 and IL-5

p38 MAP kinase inhibitor reverses stress-induced cardiac myocyte dysfunction

Stimulation of cardiac fibroblast Piezo1 channels opposes myofibroblast differentiation and induces IL-6 secretion via Ca2+-mediated p38 MAP kinase activation

Coupling of M2 muscarinic receptors to ERK MAP kinases and caldesmon phosphorylation in colonic smooth muscle

PD55-05 THERAPEUTIC EFFECTS OF P38 MAP KINASE INHIBITOR ON BLADDER DYSFUNCTION IN MICE WITH SPINAL CORD INJURY (SCI)

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