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Angiotensin II promotes nuclear oxidative damage in cardiomyocytes
Author(s) -
Parish Lauren P.,
Connelly Rhykka L.,
Schmalstieg Frank C.,
Traber Daniel L.
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.6.a1230-b
Subject(s) - peroxynitrite , reactive oxygen species , poly adp ribose polymerase , nitric oxide , oxidative stress , dna damage , apoptosis , chemistry , nitric oxide synthase , enos , angiotensin ii , reactive nitrogen species , microbiology and biotechnology , superoxide , biochemistry , biology , polymerase , enzyme , dna , receptor , organic chemistry
An elevated local concentration of angiotensin II (ATII) promotes cardiac dysfunction; consequent excessive reactive oxygen/nitrogen species (ROS/RNS) generation has been shown to trigger apoptosis in cardiomyocytes. Relevant species include nitric oxide (NO), superoxide, and peroxynitrite. Peroxynitrite, a metabolic product of NO and superoxide, has been shown to induce nuclear oxidative damage in other cell types, thereby stimulating poly(ADP‐ribose) polymerase (PARP), a DNA repair enzyme. Peroxynitrite also forms 3‐nitrotyrosated (3‐NT) proteins, a marker of cellular damage. We hypothesize that ATII triggers nuclear oxidative damage and consequent cell death in cardiomyocytes via ROS/RNS‐induced PARP and 3‐NT upregulation. HL‐1 cells were stimulated with 1μM ATII over a 4‐hour time course and analyzed confocally for ROS/RNS generation, as well as changes in nitric oxide synthase (NOS), PARP, and 3‐NT expression via western blot analyses. The results show that eNOS and nNOS are constitutively expressed in HL‐1 cardiomyocytes. Treatment with ATII caused a robust increase in ROS/RNS, as well as formation of nuclear PAR polymers and peri‐nuclear 3‐NT. Thus, the results suggest that ATII‐stimulated cardiomyocytes undergo nuclear oxidative damage via a nitric oxide pathway. Support: NIH PO12GM066312, R01GM060688, Shriners Hospitals for Children 8450, 8954, 8820