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Background Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia-reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking. Methods and Results To identify histidyl dipeptide-mediated responses in the heart, we used an integrated triomics approach, which involved genome-wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, β-fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of β-fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short- and long-chain fatty acids as well as the TCA intermediate-succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that β-fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels. Conclusions Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.
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http://dx.doi.org/10.1161/JAHA.121.023868 | DOI Listing |
J Phys Chem B
November 2024
Department of Chemistry, University of Utah, Salt Lake City, Utah 84112-0850, United States.
Metalated intact and deprotonated histidyl glycine and glycyl histidine dipeptides were investigated in the gas phase by using infrared multiple photon dissociation (IRMPD) spectroscopy with light from a free-electron laser (FEL). The dipeptides M(GlyHis), M(HisGly), [M(GlyHis-H)], and [M(HisGly-H)], where M = Zn and Cd, were probed to elucidate how the His position along the peptide chain and ligand charge state might influence the structures observed in the gas phase. Simulated annealing calculations were performed to determine energetically low-lying conformers and isomers of these structures.
View Article and Find Full Text PDFSkelet Muscle
October 2024
Center for Cardiometabolic Science, Louisville, KY, USA.
Muscle wasting is a serious complication in heart failure patients. Oxidative stress and inflammation are implicated in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE), which covalently bind with proteins and DNA and activate atrophic pathways.
View Article and Find Full Text PDFACS Sustain Chem Eng
September 2024
School of Biology, University of St Andrews, North Haugh, St Andrews KY16 9ST, U.K.
Cyclodipeptide synthases (CDPSs) are enzymes that use aminoacylated tRNAs as substrates to produce cyclic dipeptide natural products acting as anticancer and neuroprotective compounds. Many CDPSs, however, suffer from instability and poor recyclability, while enzyme immobilization can enhance catalyst efficiency and reuse. Here, the CDPS enzyme from was immobilized using three different supports: biochar from waste materials, calcium-alginate beads, and chitosan beads.
View Article and Find Full Text PDFFront Pharmacol
January 2024
Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, United States.
Oral consumption of histidyl dipeptides such as l-carnosine has been suggested to promote cardiometabolic health, although therapeutic mechanisms remain incompletely understood. We recently reported that oral consumption of a carnosine analog suppressed markers of fibrosis in liver of obese mice, but whether antifibrotic effects of carnosine extend to the heart is not known, nor are the mechanisms by which carnosine is acting. Here, we investigated whether oral carnosine was able to mitigate the adverse cardiac remodeling associated with diet induced obesity in a mouse model of enhanced lipid peroxidation (i.
View Article and Find Full Text PDFBackground: Muscle wasting is a serious complication in heart failure patients, and oxidative stress is involved in the pathogenesis of muscle wasting. Oxidative stress leads to the formation of toxic lipid peroxidation products, such as 4-hydroxy-2-nonenal (HNE) and acrolein, which causemuscle wasting. In tissues, these toxic aldehydes are metabolically removed by enzymes such asaldo keto reductases and endogenous nucleophiles, such as glutathione and carnosine.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!