| Oxidation of biological membranes and lipoproteins is a major source of bioactive aldehydes. Such aldehydes can damage cellular constituents and thereby alter tissue function. Although the pathological role of lipid-derived aldehydes is an active area of biomedical research, the effects of these aldehydes in cardiovascular disease are unclear. Accordingly, the objective of this thesis was to determine the biochemical and physiological influence of aldehydes on cardiovascular cells and tissues and assess the mechanisms of their biological effects.; The central hypothesis of this dissertation is that aldehydes perturb cellular and systemic functions via covalent protein modification and that such modifications either promote adaptive responses to oxidative stress or cause cell death. The studies presented herein demonstrate that aldehydes modify cellular proteins in diseased cardiovascular tissues derived from atherosclerosic lesions, restenotic vessels, and ischemic and failing hearts. Results obtained from this work indicate further that aldehydes induce acute cardiac dysfunction that recapitulates the phenotype of the stunned myocardium, which could be attributable to covalent protein modifications. Our investigations also demonstrate that myocardial ischemia reversibly inhibits mitochondrial metabolism of aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) and that this metabolic failure results in increased ischemic damage to mitochondrial proteins. Lipid-derived aldehydes were also found to promote autophagy, and this activation of the autophagic program was critical for the preservation of cell viability and the removal of protein-aldehyde adducts.; Aldehydes derived from lipid oxidation also caused endoplasmic reticulum (ER) stress and activated specific components of the unfolded protein response, which was associated with the formation of aldehyde adducts with ER-resident chaperone proteins. Aldehyde modifications were prevented by nitric oxide, which promoted protein glutathiolation by both nitrosothiol-mediated glutathione transfer and by protein denitrosylation. Collectively, these studies provide a fundamental understanding of the basic protein modification reactions that contribute to cardiovascular disease and, hence, could form the basis for the development of novel therapeutic strategies that prevent deleterious damage to protein nucleophiles or that promote removal of aldehyde-modified proteins. |
