Inducible nitric oxide synthase-activated mitochondrial apoptotic pathway in hypoxic and aged rat hearts.

Abstract:

BACKGROUND:Hypoxia and aging determine on mammalian cells a stress response which implies modified production of oxidants, reactive oxygen species or reactive nitrogen species at the mitochondrial level, interfering with cell-signaling proteins and inducing mitochondrial damage, apoptosis occurrence and functional consequences. OBJECTIVE:Here we report the effects of hypoxia on the in vivo morphological and biochemical response of young and aged Wistar rat hearts. METHODS:Left ventricles were excised from each experimental point and processed. Investigations of vascular endothelial growth factor (VEGF) expression and apoptotic events, mitochondrial damage, were performed by light and electron microscopy, respectively; endothelial, inducible and neuronal NOS, PKCα, pPKCα, caspase-3 expression and Apaf-1/cytochrome c complex formation were assessed by Western blotting and co-immunoprecipitation analyses, respectively. RESULTS:Besides morphological modifications, which confirm mitochondrial suffering upon hypoxia exposure in both young and aged hearts, the role played by PKCα in controlling nitric oxide synthase (NOS) protein level was investigated. Downstream PKCα activation, a dramatic iNOS expression increase, concomitant to enhanced apoptotic cell percentage and Apaf-1/cytochrome c co-immunoprecipitation, is evident in the hypoxic young, suggesting iNOS-mediated activation of the mitochondrial apoptotic pathway. CONCLUSIONS:Moreover, overexpression of iNOS and VEGF in the hypoxic young rat hearts suggests that an increased VEGF level may allow coordinated development of the lymphatic and blood vasculature, necessary for fluid homeostasis and to counteract oxidative stress. Thus the inhibition of such growth factor proposes new therapeutic possibilities for diseases associated to vascular function and for solid tumors which show pathological angiogenesis and lymphoangiogenesis.

journal_name

Gerontology

journal_title

Gerontology

authors

Zara S,Rapino M,Centurione L,di Giacomo V,Petruccelli G,Cataldi A

doi

10.1159/000299105

subject

Has Abstract

pub_date

2010-01-01 00:00:00

pages

544-52

issue

6

eissn

0304-324X

issn

1423-0003

pii

000299105

journal_volume

56

pub_type

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