Are nitric oxide-mediated protein modifications of functional significance in diabetic heart? ye'S, -NO', wh'Y-NO't?

Protein modifications effected by nitric oxide (NO) primarily in conjunction with reactive oxygen species (ROS) include tyrosine nitration, cysteine S-nitrosylation, and glutathionylation. The physiological and pathological relevance of these three modifications is determined by the amino acids on which these modifications occur -cysteine and tyrosine, for instance, ranging from altering structural integrity/catalytic activity of proteins or by altering propensity towards protein degradation. Even though tyrosine nitration is a well-established nitroxidative stress marker, instilled as a footprint of oxygen- and nitrogen-derived oxidants, newer data suggest its wider role in embryonic heart development and substantiate the need to focus on elucidating the underlying mechanisms of reversibility and specificity of tyrosine nitration. S-nitrosylation is a covalent modification in specific cysteine residues of proteins and is suggested as one of the ways in which NO contributes to its ubiquitous signalling. Several sensitive and specific techniques including biotin switch assay and mass spectrometry based analysis make it possible to identify a large number of these modified proteins, and provide a great deal of potential S-nitrosylation sites. The number of studies that have documented nitrated proteins in diabetic heart is relatively much less compared to what has been published in the normal physiology and other cardiac pathologies. Nevertheless, elucidation of nitrated proteome of diabetic heart has revealed the presence of many mitochondrial and cytosolic proteins of functional importance. But, the existence of different models of diabetes and analyses at diverse stages of this disease have impeded scientists from gaining insights that would be essential to understand the cardiac complications during diabetes. This review summarizes NO mediated protein modifications documented in normal and abnormal heart physiology including diabetes.

Honokiol regulates mitochondrial substrate utilization and cellular fatty acid metabolism in diabetic mice heart.

Type 2 diabetes mellitus is strongly associated with cardiac mitochondrial dysfunction, which is one of the main reasons for cardiovascular diseases. Among the mitochondrial metabolic changes, fatty acid metabolism is of great importance as cardiac tissues depend primarily on fatty acids. Honokiol, a constituent of Magnolia tree bark extract, is reported to strongly influence cardiac mitochondrial functions, via various mechanisms. The current study showed that honokiol decreased fatty acid-mediated complex I respiration and increased carbohydrate-mediated complex I and II respiration in diabetic C57BL/6 mice cardiac mitochondria. It was also found that honokiol treatment decreased expression of Cluster of Differentiation 36, AMP-activated kinases and nuclear transcription factors like, Peroxisome proliferator-activated receptor γ co-activator 1α/ß and Peroxisome proliferator-activated receptor α, surrogating the evidence of decreased fatty acid-mediated complex I respiration. Honokiol treatment also reduced the levels of mitochondrial acetylated proteins, suggesting the possible action of honokiol via acetylation/deacetylation mechanism of regulation of protein functions in diabetic mitochondria. The antioxidant effect of honokiol is evidenced by the augmented expression of Manganese super oxide dismutase. In conclusion, honokiol imparts beneficial effect on diabetic cardiac mitochondria by decreasing the oxidant burden via regulating mitochondrial fatty acid respiration and expression of oxidant response factors.