First 11 pages of thesis. - OPUS - Universität Würzburg

1.7 Aim of the study
As described in the previous section, NOS isoforms differ in their
physiological regulation, cellular compartment of expression, sub cellular
localization and catalytic activity suggesting a complex involvement in
atherosclerosis development. Therefore, it is a considerable challenge to
discern the role of each NOS isoform in atherosclerosis development, as all
three NOS isoforms are expressed in the vessel wall. Unfortunately, the use of
pharmacologic NOS inhibitors is limited by their inability to selectively and fully
inhibit each NOS isoform. In contrast, gene knockout models allow the
dissection of the distinct roles of each NOS isoform in vascular disease. In the
past, we crossed eNOS ko, nNOS ko and iNOS ko mice with atherosclerotic
apoE ko mice, generating apoE/eNOS dko, apoE/nNOS dko and apoE/iNOS
dko mice respectively, to test the contribution of each NOS isoform in diet
induced atherosclerosis.
Our previous experiments revealed that eNOS 149 and nNOS 165 are anti
atherosclerotic as genetic deletion of these enzymes resulted in accelerated
atherosclerosis in apoE ko mice. In contrast, genetic deletion of iNOS resulted
in a significant reduction of lesion formation suggesting that iNOS is
proatherogenic 180 . The contribution of the NOS isoform with regards to local
superoxide and nitric oxide in atherosclerosis is currently unknown. However,
detailed information about the radical production by each NOS isoform is of key
importance to understand the pathomechanism involved in NOS mediated
modulation of atherosclerosis development.
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