Carnosine protects cardiac myocytes against lipid peroxidation products

Abstract

Endogenous histidyl dipeptides such as carnosine (β-alanine-L-histidine) form conjugates with lipid peroxidation products such as 4-hydroxy-trans-2-nonenal (HNE and acrolein), chelate metals, and protect against myocardial ischemic injury. Nevertheless, it is unclear whether these peptides protect against cardiac injury by directly reacting with lipid peroxidation products. Hence, to examine whether changes in the structure of carnosine could affect its aldehyde reactivity and metal chelating ability, we synthesized methylated analogs of carnosine, balenine (β-alanine-Nτ-methylhistidine) and di-methylbalenine (DMB), and measured their aldehyde reactivity and metal chelating properties. We found that methylation of Nτ residue of imidazole ring (balenine) or trimethylation of carnosine backbone at Nτ residue of imidazole ring and terminal amine group dimethyl balenine (DMB) abolishes the ability of these peptides to react with HNE. Incubation of balenine with acrolein resulted in the formation of single product (m/z 297), whereas DMB did not react with acrolein. In comparison with carnosine, balenine exhibited moderate acrolein quenching capacity. The Fe2+chelating ability of balenine was higher than carnosine, whereas DMB lacked chelating capacity. Pretreatment of cardiac myocytes with carnosine increased the mean lifetime of myocytes superfused with HNE or acrolein compared with balenine or DMB. Collectively, these results suggest that carnosine protects cardiac myocytes against HNE and acrolein toxicity by directly reacting with these aldehydes. This reaction involves both the amino group of β-alanyl residue and the imidazole residue of L-histidine. Methylation of these sites prevents or abolishes the aldehyde reactivity of carnosine, alters its metal-chelating property, and diminishes its ability to prevent electrophilic injury.

Carnosine synthase deficiency is compatible with normal skeletal muscle and olfactory function but causes reduced olfactory sensitivity in aging mice

“…Because carnosine is not synthesized in the proliferating basal cells, it seems unlikely that Carns1-deficiency directly affects these cells, especially in view of the normal level of Pax6 positive precursor cells in Carns1(-/-) OE. A property of carnosine that could potentially support survival of ORN, is of course the general anti-oxidant activity that has been demonstrated in various studies (25,(49)(50)(51). Though the in vivo anti-oxidative activity of carnosine has been questioned by others (52).…”

Metabolic Profiling Associates with Disease Severity in Nonischemic Dilated Cardiomyopathy

“…It acts as a protective agent for contracting muscles and cardiomyocytes and is, therefore, suggested as a possible supplement in patients with HF. 35 Sialic acid is the common name for compounds derived from neuraminic acid, and it occurs mainly at terminal positions of glycoproteins (sialylation). Sialic acid has been well described in studies of cardiovascular disease as a marker of systemic inflammation and is a predictor of mortality.…”

Carnosine Supplementation Enhances Post Ischemic Hind Limb Revascularization

“…Among the naturally occurring histidyl dipeptides, carnosine is the most abundant in the human skeletal muscle, whereas its natural analogs such as anserine (β-alanine-N-π-histidine) and balenine (β-alanine-N-τ histidine) are found in other avian and mammalian species (Boldyrev et al, 2013). These dipeptides are multifunctional which have the capacities to chelate transition metals, such as Cu 2+ and Fe 2+ , sequester lipid peroxidation products, such as 4-hydroxy trans -2-nonenal (HNE), act as antioxidants, and buffer intracellular pH (Hipkiss, 2009; Baba et al, 2013; Boldyrev et al, 2013; Zhao et al, 2018; Ihara et al, 2019). In mammalian tissues, carnosine synthesis is catalyzed by the ATP ligase enzyme – carnosine synthetase (ATPGD1) (Drozak et al, 2010), and its homeostasis within the muscle is maintained by a complex interplay between transporters (PHT, PEPT2, and TAUT) (Everaert et al, 2013a) and hydrolases (CNDP1 and 2) (Teufel et al, 2003).…”