Hypoxia, angiotensin-II, and norepinephrine mediated apoptosis is stimulus specific in canine failed cardiomyocytes: a role for p38 MAPK, Fas-L and cyclin D1.

Abstract

BACKGROUND:

Apoptosis may contribute to the myocardial dysfunction associated with heart failure (HF). Activation of the p38 MAPK cascade can induce apoptosis in non-cardiac cells through increased expression of Fas-L, or through decreased expression of cyclin D(1).

AIMS:

We tested the hypothesis that hypoxia (HX), angiotensin-II (A-II) and norepinephrine (NEPI) can mediate apoptosis by activating p38 MAPK, and thus initiating stimulus specific changes in Fas-L and cyclin D(1) expression in failing cardiomyocytes.

METHODS AND RESULTS:

Cardiomyocytes isolated from ten dogs with HF induced by coronary microembolizations were subjected to HX or A-II or NEPI with and without a p38 MAPK inhibitor (SB 203580). TUNEL staining for DNA fragmentation and Western blots for p38 MAPK, Fas-L and cyclin D(1) detection were performed. HX-induced apoptosis was associated with increased Fas-L expression, A-II-induced apoptosis was associated with increased Fas-L and decreased cyclin D(1) expression, and NEPI-induced apoptosis was associated with decreased cyclin D(1) expression. Inhibition of p38 MAPK activity attenuated stress-induced apoptosis in all experiments and reversed changes in Fas-L and cyclin D(1) expression.

CONCLUSIONS:

HX, A-II and NEPI mediate apoptosis in failing cardiomyocytes via different effects on Fas-L and cyclin D(1) expression. Inhibition of p38 MAPK reversed these effects, suggesting that apoptosis induced by HX, A-II and NEPI involves activation of p38 MAPK upstream from Fas-L and cyclin D(1).

• Authors: Victor G Sharov, Anastassia Todor, George Suzuki, Hideaki Morita, Elaine J Tanhehco, Hani N Sabbah
• Journal: European journal of heart failure (Eur J Heart Fail) Vol. 5 Issue 2 Pg. 121-9 (Mar 2003) ISSN: 1388-9842 [Print] England
• PMID: 12644001 (Publication Type: Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Fas Ligand Protein
• Membrane Glycoproteins
• Angiotensin II
• Cyclin D1
• Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Norepinephrine

Topics

• Angiotensin II (pharmacology)
• Animals
• Apoptosis (drug effects, physiology)
• Cyclin D1 (drug effects, physiology)
• Disease Models, Animal
• Dogs
• Fas Ligand Protein
• Follow-Up Studies
• Heart Failure (metabolism, physiopathology)
• Hypoxia (metabolism, physiopathology)
• Incidence
• Membrane Glycoproteins (drug effects, physiology)
• Mitogen-Activated Protein Kinases (drug effects, physiology)
• Models, Cardiovascular
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Norepinephrine (pharmacology)
• p38 Mitogen-Activated Protein Kinases