Hypoxic induction of CCN2 mRNA through p38 MAP kinase activation in the human chondrosarcoma‐derived cell line, HCS‐2/8

Myocardial dysfunction leading to dilated cardiomyopathy has been documented with surprisingly high frequency in human immunodeficiency virus (HIV)-infected individuals. p38 MAP kinase has been implicated as a mediator of myocardial dysfunction. We previously reported p38 MAP kinase activation by the HIV coat protein gp120 in neonatal rat cardiac myocytes. We now report the direct inotropic effects of HIV gp120 on adult rat ventricular myocytes (ARVM). ARVM were continuously superfused with gp120, and percent fractional shortening (FS) was determined by automated border detection and simultaneous intracellular ionized free Ca2+concentration ([Ca2+]i) measured by fura 2-AM fluorescence: gp120 alone increased FS and increased [Ca2+]iwithin 5 min and then depressed FS without a decrease in [Ca2+]iby 20–60 min, which persisted for at least 2 h. Exposure of ARVM to gp120 also resulted in the phosphorylation of the upstream regulator of p38 MAP kinase MKK3/6, p38 MAP kinase itself, and its downstream effector, ATF-2, over a similar time course. ERK (p44/42) and JNK stress signaling pathways were not similarly activated. The effects of the p38 MAP kinase inhibitor were concentration dependent. SB-203580 (10 μM) blocked both p38 MAP kinase phosphorylation and the delayed negative inotropic effect of gp120. SB-203580 (5 μM) selectively blocked phosphorylation of ATF-2 without blocking the phosphorylation of MKK3/6 or p38 MAP kinase itself. SB-203580 (5 μM) administered before, with, or after gp120 blocked the negative inotropic effect of gp120 in ARVM. p38 MAP kinase activation may be a common stress-response mechanism contributing to myocardial dysfunction in HIV and other nonischemic as well as ischemic cardiomyopathies.

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Ikarugamycin induces DNA damage, intracellular calcium increase, p38 MAP kinase activation and apoptosis in HL-60 human promyelocytic leukemia cells

Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis ◽

10.1016/j.mrfmmm.2011.03.001 ◽

2011 ◽

Vol 709-710 ◽

pp. 60-66 ◽

Cited By ~ 26

Author(s):

Ruxandra Popescu ◽

Elke Hannelore Heiss ◽

Franziska Ferk ◽

Andrea Peschel ◽

Siegfried Knasmueller ◽

...

Keyword(s):

Dna Damage ◽

Map Kinase ◽

Intracellular Calcium ◽

P38 Map Kinase ◽

Promyelocytic Leukemia ◽

Leukemia Cells ◽

Kinase Activation

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Optimal reactive oxygen species concentration and p38 MAP kinase are required for coronary collateral growth

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.01330.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. H2729-H2736 ◽

Cited By ~ 52

Author(s):

Petra Rocic ◽

Christopher Kolz ◽

Ryan Reed ◽

Barry Potter ◽

William M. Chilian

Keyword(s):

Map Kinase ◽

Tube Formation ◽

Oxidase Inhibitor ◽

P38 Map Kinase ◽

Collateral Flow ◽

Vascular Endothelial ◽

Kinase Activation ◽

Normal Zone ◽

Collateral Growth ◽

Endothelial Growth Factor

Reactive oxygen species (ROS) are implicated in coronary collateral growth (CCG). We evaluated the requirement for ROS in human coronary artery endothelial cell (HCAEC) tube formation, CCG in vivo, and signaling (p38 MAP kinase) by which ROS may stimulate vascular growth. The flavin-containing oxidase inhibitor diphenyleneiodonium (DPI) or the superoxide dismutase inhibitor diethyldithiocarbamate (DETC) blocked vascular endothelial growth factor-induced HCAEC tube formation in Matrigel. We assessed the effect of DPI and DETC on CCG in a rat model of repetitive ischemia (RI) (40 s left anterior descending coronary artery occlusion every 20 min for 2 h 20 min, 3 times/day, 10 days). DPI or DETC was given intraperitoneally, or the NAD(P)H oxidase inhibitor apocynin was given in drinking water. Collateral-dependent flow (measured by using microspheres) was expressed as a ratio of normal and ischemic zone flows. In sham-operated rats, collateral flow in the ischemic zone was 18 ± 6% of normal zone; in the RI group, collateral flow in the ischemic zone was 83 ± 5% of normal zone. DPI prevented the increase in collateral flow after RI (25 ± 4% of normal zone). Similar results were obtained with apocynin following RI (32 ± 7% of that in the normal zone). DETC achieved similar results (collateral flow after RI was 21 ± 2% of normal zone). DPI and DETC blocked RI-induced p38 MAP kinase activation in response to vascular endothelial growth factor and RI. These results demonstrate a requirement for optimal ROS concentration in HCAEC tube formation, CCG, and p38 MAP kinase activation. p38 MAP kinase inhibition prevented HCAEC tube formation and partially blocked RI-induced CCG (42 ± 7% of normal zone flow), indicating that p38 MAP kinase is a critical signaling mediator of CCG.

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