TARGETING INFLAMMATORY MICROENVIROMENT IN ATHEROSCLEROSIS BY INDUCIBLE NITRIC OXIDE SYNTHASE INHIBITORS
Progetto Atherosclerosis is the major underlying cause of cardiovascular diseases, cerebrovascular diseases, and
peripheral vascular diseases, and is strongly associated with high morbidity and mortality rates. No current
resolutive therapies are available, thus there is an urgent need to explore new innovative strategies to
counteract atherosclerosis. Immunotherapy has been proposed to treat unresolved inflammation in
atherosclerotic plaque. While several clinical trials underpinned the efficacy of immunotherapy, it was
generally associated with increased infection rates. Here we propose an entirely new approach for
intervention in plaque inflammation, inspired by compelling findings on the key role of inducible nitric oxide
synthase (iNOS) in adverse macrophage-endothelial communication in plaque destabilization, and on the
immunomodulatory activity showed by new potent iNOS inhibitors, developed by consortium members. In
this proposal we aim to validate this concept and target the inflammatory microenvironment associated to the
atherosclerotic plaque rupture, and ensuing plaque thrombosis. To this end, five different European partners
and an extra-European Collaborator with highly complementary competences and expertise in medicinal
chemistry (Italy and Spain-UniGR), nanocarrier design and application (Spain-UniZAR) and cardiovascular
inflammation (Netherlands, Australia), will join forces. The team will screen a panel of iNOS inhibitors, which
will be tested for their ability to tone macrophages activation status and their crosstalk with endothelial cells
(via endovesicles or direct interaction). In parallel, an innovative nanocarrier platforms will be refined and
tested to specifically deliver selected leads to plaque macrophages and test their efficacy ex vivo. The
inhibition of iNOS during atherogenesis could represent an innovative therapeutical strategy for CDVs, to
reduce the vascular inflammation associated to atherosclerosis, rebalancing vessels homeostasis.