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Published on: September 22, 2017
Cardiopulmonary bypass reduces peripheral microvascular contractile function by inhibition of mitogen-activated
Tanveer A Khan1, Cesario Bianchi, Eugenio G Araujo
1Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Background:
Mitogen-activated protein kinases (MAPK) have been implicated in pathophysiologic responses to cardiopulmonary bypass (CPB). MAPK are deactivated by phosphatases, such as MAPK phosphatase-1 (MKP-1). We hypothesized that MAPK mediate peripheral microvascular contractile dysfunction caused by CPB in humans.
Methods:
Skeletal muscle was harvested before and after CPB. Protein levels of MKP-1 and activated extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 were measured. MKP-1 gene expression was measured. Peripheral microvessel responses to vasopressors were studied by videomicroscopy. Contractile function also was measured after MAPK inhibition with PD98059 (ERK1/2) and SB203580 (p38). ERK1/2, p38, and MKP-1 were localized by immunohistochemistry and in situ hybridization.
Results:
ERK1/2 and p38 activity was decreased in peripheral tissue after CPB. MKP-1 was increased after CPB. Contractile responses of peripheral arterioles to phenylephrine and vasopressin were decreased after CPB. Microvessel reactivity also was reduced after treatment with PD98059 and SB203580. ERK1/2, p38, and MKP-1 localized to peripheral arterioles in tissue sections.
Conclusions:
CPB reduces ERK1/2 and p38 activity in peripheral tissue, potentially by MKP-1. Contractile responses of peripheral arterioles to phenylephrine and vasopressin are dependent on ERK1/2 and p38 and are decreased after CPB. These results suggest that alterations in MAPK pathways in part regulate peripheral microvascular dysfunction after CPB in humans.
Insights
Cardiopulmonary bypass (CPB) impairs microvascular function by altering mitogen-activated protein kinase (MAPK) pathways. Increased MAPK phosphatase-1 (MKP-1) after CPB reduces extracellular signal-regulated kinase 1/2 (ERK1/2) and p38 activity, leading to contractile dysfunction.
Area of Science:
- Cardiovascular Physiology
- Molecular Biology
- Surgical Research
Background:
- Mitogen-activated protein kinases (MAPK) are crucial in cellular responses to cardiopulmonary bypass (CPB).
- MAPK phosphatase-1 (MKP-1) deactivates MAPKs.
- MAPK involvement in CPB-induced peripheral microvascular dysfunction is hypothesized.
Purpose of the Study:
- To investigate the role of MAPK in CPB-induced peripheral microvascular contractile dysfunction in humans.
- To assess changes in MAPK and MKP-1 levels and activity following CPB.
Main Methods:
- Skeletal muscle biopsies before and after CPB.
- Measurement of MKP-1, activated extracellular signal-regulated kinase 1/2 (ERK1/2), and p38 protein levels and gene expression.
- Videomicroscopy to assess peripheral microvessel responses to vasopressors.
- Assessment of contractile function after MAPK inhibition.
Main Results:
- CPB decreased ERK1/2 and p38 activity and increased MKP-1 in peripheral tissue.
- Peripheral arteriole contractile responses to phenylephrine and vasopressin were reduced post-CPB.
- Microvessel reactivity was diminished following MAPK inhibition.
Conclusions:
- CPB reduces peripheral ERK1/2 and p38 activity, potentially mediated by MKP-1.
- Peripheral arteriole function is dependent on ERK1/2 and p38 activity, which is impaired after CPB.
- MAPK pathway alterations contribute to peripheral microvascular dysfunction following CPB in humans.
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