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alpha(4)-integrin mediates neutrophil-induced free radical injury to cardiac myocytes.

Poon BY, Ward CA, Cooper CB, Giles WR, Burns AR, Kubes P - J. Cell Biol. (2001)

Bottom Line: Myocyte shortening was decreased by 30-50% and rates of contraction and relaxation were reduced by 30% within the first 10 min.These findings demonstrate that profound molecular changes occur within PMNs as they emigrate, such that CD18 and associated intracellular signaling pathways leading to oxidant production are uncoupled and newly expressed alpha(4)-integrin functions as the ligand that signals oxidant production.The results also provide pathological relevance as the emigrated PMNs have the capacity to injure cardiac myocytes through the alpha(4)-integrin-coupled NADPH oxidase pathway that can be inhibited by extracellular, but not intracellular SOD.

View Article: PubMed Central - PubMed

Affiliation: Immunology Research Group, University of Calgary, Calgary, Alberta T2N 1N4, Canada.

ABSTRACT
Previous work has demonstrated that circulating neutrophils (polymorphonuclear leukocytes [PMNs]) adhere to cardiac myocytes via beta(2)-integrins and cause cellular injury via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme system. Since PMNs induced to leave the vasculature (emigrated PMNs) express the alpha(4)-integrin, we asked whether (a) these PMNs also induce myocyte injury via NADPH oxidase; (b) beta(2)-integrins (CD18) still signal oxidant production, or if this process is now coupled to the alpha(4)-integrin; and (c) dysfunction is superoxide dependent within the myocyte or at the myocyte-PMN interface. Emigrated PMNs exposed to cardiac myocytes quickly induced significant changes in myocyte function. Myocyte shortening was decreased by 30-50% and rates of contraction and relaxation were reduced by 30% within the first 10 min. Both alpha(4)-integrin antibody (Ab)-treated PMNs and NADPH oxidase-deficient PMNs were unable to reduce myocyte shortening. An increased level of oxidative stress was detected in myocytes within 5 min of PMN adhesion. Addition of an anti-alpha(4)-integrin Ab, but not an anti-CD18 Ab, prevented oxidant production, suggesting that in emigrated PMNs the NADPH oxidase system is uncoupled from CD18 and can be activated via the alpha(4)-integrin. Addition of exogenous superoxide dismutase (SOD) inhibited all parameters of dysfunction measured, whereas overexpression of intracellular SOD within the myocytes did not inhibit the oxidative stress or the myocyte dysfunction caused by the emigrated PMNs. These findings demonstrate that profound molecular changes occur within PMNs as they emigrate, such that CD18 and associated intracellular signaling pathways leading to oxidant production are uncoupled and newly expressed alpha(4)-integrin functions as the ligand that signals oxidant production. The results also provide pathological relevance as the emigrated PMNs have the capacity to injure cardiac myocytes through the alpha(4)-integrin-coupled NADPH oxidase pathway that can be inhibited by extracellular, but not intracellular SOD.

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Change in rates of (A) contraction (+dP/dt) and (B) relaxation (−dP/dt) in myocytes under baseline conditions after 10 min in control (no PMNs, n = 6; WT PMNs, n = 7; and NADPH oxidase KO PMNs, n = 6). +, P < 0.05 relative to respective baseline.
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Figure 3: Change in rates of (A) contraction (+dP/dt) and (B) relaxation (−dP/dt) in myocytes under baseline conditions after 10 min in control (no PMNs, n = 6; WT PMNs, n = 7; and NADPH oxidase KO PMNs, n = 6). +, P < 0.05 relative to respective baseline.

Mentions: Data summarizing the maximal rates of contraction and relaxation of myocytes within these groups are shown in Fig. 3. The maximal rate of contraction and relaxation remained constant in the control group throughout the entire 10-min experimental period (n = 6, P = NS). The addition of WT emigrated PMNs decreased both contraction and relaxation rates by ∼30% from baseline at 10 min (n = 6, P < 0.05). It is noteworthy that changes in the rate of contraction and relaxation did not occur at 5 min of PMN exposure, the time at which a decrease in cell shortening was observed. PMNs from NADPH oxidase–deficient mice did not alter either contraction or relaxation rates in these myocytes. Late in most experiments, after exposure to PMNs, myocytes also became dysrythmic. Specifically, control myocytes alone showed no myocyte dysrythmia (n = 6), but the addition of WT PMNs caused five of the seven myocytes recorded to become dysrythmic. When PMNs from NADPH oxidase–deficient mice were added to the myocytes, only one of the six myocytes in this group showed any dysrythmia.


alpha(4)-integrin mediates neutrophil-induced free radical injury to cardiac myocytes.

Poon BY, Ward CA, Cooper CB, Giles WR, Burns AR, Kubes P - J. Cell Biol. (2001)

Change in rates of (A) contraction (+dP/dt) and (B) relaxation (−dP/dt) in myocytes under baseline conditions after 10 min in control (no PMNs, n = 6; WT PMNs, n = 7; and NADPH oxidase KO PMNs, n = 6). +, P < 0.05 relative to respective baseline.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2198813&req=5

Figure 3: Change in rates of (A) contraction (+dP/dt) and (B) relaxation (−dP/dt) in myocytes under baseline conditions after 10 min in control (no PMNs, n = 6; WT PMNs, n = 7; and NADPH oxidase KO PMNs, n = 6). +, P < 0.05 relative to respective baseline.
Mentions: Data summarizing the maximal rates of contraction and relaxation of myocytes within these groups are shown in Fig. 3. The maximal rate of contraction and relaxation remained constant in the control group throughout the entire 10-min experimental period (n = 6, P = NS). The addition of WT emigrated PMNs decreased both contraction and relaxation rates by ∼30% from baseline at 10 min (n = 6, P < 0.05). It is noteworthy that changes in the rate of contraction and relaxation did not occur at 5 min of PMN exposure, the time at which a decrease in cell shortening was observed. PMNs from NADPH oxidase–deficient mice did not alter either contraction or relaxation rates in these myocytes. Late in most experiments, after exposure to PMNs, myocytes also became dysrythmic. Specifically, control myocytes alone showed no myocyte dysrythmia (n = 6), but the addition of WT PMNs caused five of the seven myocytes recorded to become dysrythmic. When PMNs from NADPH oxidase–deficient mice were added to the myocytes, only one of the six myocytes in this group showed any dysrythmia.

Bottom Line: Myocyte shortening was decreased by 30-50% and rates of contraction and relaxation were reduced by 30% within the first 10 min.These findings demonstrate that profound molecular changes occur within PMNs as they emigrate, such that CD18 and associated intracellular signaling pathways leading to oxidant production are uncoupled and newly expressed alpha(4)-integrin functions as the ligand that signals oxidant production.The results also provide pathological relevance as the emigrated PMNs have the capacity to injure cardiac myocytes through the alpha(4)-integrin-coupled NADPH oxidase pathway that can be inhibited by extracellular, but not intracellular SOD.

View Article: PubMed Central - PubMed

Affiliation: Immunology Research Group, University of Calgary, Calgary, Alberta T2N 1N4, Canada.

ABSTRACT
Previous work has demonstrated that circulating neutrophils (polymorphonuclear leukocytes [PMNs]) adhere to cardiac myocytes via beta(2)-integrins and cause cellular injury via the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme system. Since PMNs induced to leave the vasculature (emigrated PMNs) express the alpha(4)-integrin, we asked whether (a) these PMNs also induce myocyte injury via NADPH oxidase; (b) beta(2)-integrins (CD18) still signal oxidant production, or if this process is now coupled to the alpha(4)-integrin; and (c) dysfunction is superoxide dependent within the myocyte or at the myocyte-PMN interface. Emigrated PMNs exposed to cardiac myocytes quickly induced significant changes in myocyte function. Myocyte shortening was decreased by 30-50% and rates of contraction and relaxation were reduced by 30% within the first 10 min. Both alpha(4)-integrin antibody (Ab)-treated PMNs and NADPH oxidase-deficient PMNs were unable to reduce myocyte shortening. An increased level of oxidative stress was detected in myocytes within 5 min of PMN adhesion. Addition of an anti-alpha(4)-integrin Ab, but not an anti-CD18 Ab, prevented oxidant production, suggesting that in emigrated PMNs the NADPH oxidase system is uncoupled from CD18 and can be activated via the alpha(4)-integrin. Addition of exogenous superoxide dismutase (SOD) inhibited all parameters of dysfunction measured, whereas overexpression of intracellular SOD within the myocytes did not inhibit the oxidative stress or the myocyte dysfunction caused by the emigrated PMNs. These findings demonstrate that profound molecular changes occur within PMNs as they emigrate, such that CD18 and associated intracellular signaling pathways leading to oxidant production are uncoupled and newly expressed alpha(4)-integrin functions as the ligand that signals oxidant production. The results also provide pathological relevance as the emigrated PMNs have the capacity to injure cardiac myocytes through the alpha(4)-integrin-coupled NADPH oxidase pathway that can be inhibited by extracellular, but not intracellular SOD.

Show MeSH
Related in: MedlinePlus