Acetylation has recently emerged as an important mechanism for controlling a broad array of proteins mediating cellular adaptation to metabolic fuels. Acetylation is governed, in part, by SIRTs (sirtuins), class III NAD+-dependent deacetylases that regulate lipid and glucose metabolism in liver during fasting and aging. However, the role of acetylation or SIRTs in pathogenic hepatic fuel metabolism under nutrient excess is unknown. In the present study, we isolated acetylated proteins from total liver proteome and observed 193 preferentially acetylated proteins in mice fed on an HFD (high-fat diet) compared with controls, including 11 proteins not previously identified in acetylation studies. Exposure to the HFD led to hyperacetylation of proteins involved in gluconeogenesis, mitochondrial oxidative metabolism, methionine metabolism, liver injury and the ER (endoplasmic reticulum) stress response. Livers of mice fed on the HFD had reduced SIRT3 activity, a 3-fold decrease in hepatic NAD+ levels and increased mitochondrial protein oxidation. In contrast, neither SIRT1 nor histone acetyltransferase activities were altered, implicating SIRT3 as a dominant factor contributing to the observed phenotype. In Sirt3−/− mice, exposure to the HFD further increased the acetylation status of liver proteins and reduced the activity of respiratory complexes III and IV. This is the first study to identify acetylation patterns in liver proteins of HFD-fed mice. Our results suggest that SIRT3 is an integral regulator of mitochondrial function and its depletion results in hyperacetylation of critical mitochondrial proteins that protect against hepatic lipotoxicity under conditions of nutrient excess.

Cells are exposed during their lifetimes to an array of physical forces ranging from those generated by association with other cells and extracellular matrices to the constant forces placed on cells by gravity. Alterations in these forces, either with differentiation and development or changes in activity or behavior, result in modifications in the biochemistry and adaptation in structure and function of cells. Also, a variety of differentiated cells have unique shapes that relate to extremely specialized functions, with structure and function emerging concurrently. These observations lead to the concept that the forces perceived by cells may dictate their shape, and the combined effects of external physical stimuli and internal forces responsible for maintaining cell shape may stimulate alterations in cellular biochemistry. This review examines the state of our knowledge concerning the mechanisms through which physical forces are converted to biochemical signals (mechanotransduction), and speculates on the molecular structures that may be involved in mechanotransduction.

Objective: This study was performed to assess the utility of selective small-molecule inhibitors of class I HDACs in a preclinical model of pulmonary hypertension. Methods and Results:Rats were exposed to hypobaric hypoxia for 3 weeks in the absence or presence of a benzamide HDAC inhibitor, MGCD0103, which selectively inhibits class I HDACs 1, 2, and 3. The compound reduced pulmonary arterial pressure more dramatically than tadalafil, a standard-of-care therapy for human pulmonary hypertension that functions as a vasodilator. MGCD0103 improved pulmonary artery acceleration time and reduced systolic notching of the pulmonary artery flow envelope, which suggests a positive impact of the HDAC inhibitor on pulmonary vascular remodeling and stiffening. Similar results were obtained with an independent class I HDAC-selective inhibitor, MS-275. Reduced pulmonary arterial pressure in MGCD0103-treated animals was associated with blunted pulmonary arterial wall thickening because of suppression of smooth muscle cell proliferation. Right ventricular function was maintained in MGCD0103-treated animals. Although the class I HDAC inhibitor only modestly reduced right ventricular hypertrophy, it had multiple beneficial effects on the right ventricle, which included suppression of pathological gene expression, inhibition of proapoptotic caspase activity, and repression of proinflammatory protein expression. Key Words: histone deacetylase Ⅲ pulmonary hypertension Ⅲ proliferation Ⅲ gene expression Ⅲ signaling pathways I n patients with pulmonary hypertension (PH), restricted blood flow through the pulmonary arterial circulation due to increased pulmonary vascular resistance often results in right-sided heart failure. Despite recent advances in the treatment of PH, the 5-year mortality rate for individuals with this disease still approaches 50%, which highlights an urgent need for novel therapeutics. 1 Current standards of care for patients with PH typically involve the use of vasoactive drugs, including endothelin receptor antagonists, phosphodiesterase type 5 inhibitors, and prostacyclins. More effective therapeutic strategies will likely be based on the combined use of vasodilators and agents that target distinct pathogenic mechanisms in PH, such as pulmonary vascular inflammation and fibrosis, as well as aberrant proliferation of smooth muscle cells, endothelial cells, and fibroblasts in the lung vasculature. 2 Additionally, because right ventricular (RV) failure is the cause of death in the majority of PH patients, 3,4 and it is unclear whether standards of care for left ventricular Original received October 8, 2011; revision received January 11, 2012; accepted January 18, 2012. In December 2011 HDACs control cell proliferation, inflammation, and fibrosis by catalyzing removal of acetyl groups from lysine residues in a variety of proteins. The 18 mammalian HDACs are encoded by distinct genes and are grouped into 4 classes. 6 Two broad-spectrum HDAC inhibitors are approved for the treatment of cancer. One of these compounds,...

This study was conducted to examine the role of myocardial ATP-sensitive potassium (K ATP ) channels in exercise-induced protection from ischaemia-reperfusion (I-R) injury. Female rats were either sedentary (Sed) or exercised for 12 weeks (Tr). Hearts were excised and underwent a 1-2 h regional I-R protocol. Prior to ischaemia, hearts were subjected to pharmacological blockade of the sarcolemmal K ATP channel with HMR 1098 (SedHMR and TrHMR), mitochondrial blockade with 5-hydroxydecanoic acid (5HD; Sed5HD and Tr5HD), or perfused with buffer containing no drug (Sed and Tr). Infarct size was significantly smaller in hearts from Tr animals (35.4 ± 2.3 versus 44.7 ± 3.0% of the zone at risk for Tr and Sed, respectively). Mitochondrial K ATP blockade did not abolish the training-induced infarct size reduction (30.0 ± 3.4 versus 38.0 ± 2.6 in Tr5HD and Sed5HD, respectively); however, sarcolemmal K ATP blockade completely eradicated the training-induced cardioprotection. Infarct size was 71.2 ± 3.3 and 64.0 ± 2.4% of the zone at risk for TrHMR and Sed HMR. The role of sarcolemmal K ATP channels in Tr-induced protection was also supported by significant increases in both subunits of the sarcolemmal K ATP channel following training. LV developed pressure was better preserved in hearts from Tr animals, and was not influenced by addition of HMR 1098. 5HD decreased pressure development regardless of training status, from 15 min of ischaemia through the duration of the protocol. This mechanical dysfunction was likely to be due to a 5HD-induced increase in myocardial Ca 2+ content following I-R. The major findings of the present study are: (1) unlike all other known forms of delayed cardioprotection, infarct sparing following chronic exercise was not abolished by 5HD; (2) pharmacological blockade of the sarcolemmal K ATP channel nullified the cardioprotective benefits of exercise training; and (3) increased expression of sarcolemmal K ATP channels was observed following chronic training.