Cardiospecific Overexpression of ATPGD1 (Carnosine Synthase) Increases Histidine Dipeptide Levels and Prevents Myocardial Ischemia Reperfusion Injury

Abstract

BACKGROUND Myocardial ischemia reperfusion (I/R) injury is associated with complex pathophysiological changes characterized by pH imbalance, the accumulation of lipid peroxidation products acrolein and 4‐hydroxy trans ‐2‐nonenal, and the depletion of ATP levels. Cardioprotective interventions, designed to address individual mediators of I/R injury, have shown limited efficacy. The recently identified enzyme ATPGD1 (Carnosine Synthase), which synthesizes histidyl dipeptides such as carnosine, has the potential to counteract multiple effectors of I/R injury by buffering intracellular pH and quenching lipid peroxidation products and may protect against I/R injury . METHODS AND RESULTS We report here that β‐alanine and carnosine feeding enhanced myocardial carnosine levels and protected the heart against I/R injury. Cardiospecific overexpression of ATPGD 1 increased myocardial histidyl dipeptides levels and protected the heart from I/R injury. Isolated cardiac myocytes from ATPGD 1‐transgenic hearts were protected against hypoxia reoxygenation injury. The overexpression of ATPGD 1 prevented the accumulation of acrolein and 4‐hydroxy trans ‐2‐nonenal–protein adducts in ischemic hearts and delayed acrolein or 4‐hydroxy trans ‐2‐nonenal–induced hypercontracture in isolated cardiac myocytes. Changes in the levels of ATP , high‐energy phosphates, intracellular pH, and glycolysis during low‐flow ischemia in the wild‐type mice hearts were attenuated in the ATPGD 1‐transgenic hearts. Two natural dipeptide analogs (anserine and balenine) that can either quench aldehydes or buffer intracellular pH , but not both, failed to protect against I/R injury. CONCLUSIONS Either exogenous administration or enhanced endogenous formation of histidyl dipeptides prevents I/R injury by attenuating changes in intracellular pH and preventing the accumulation of lipid peroxidation derived aldehydes.

Histidine dipeptides are key regulators of excitation-contraction coupling in cardiac muscle: Evidence from a novel CARNS1 knockout rat model

“…Our novel approach to study the role of HCDs to normal function shows that HCDs are important regulators of EC coupling in cardiac muscle, where it enhances Ca 2+ amplitude during contraction and speeds up Ca 2+ reuptake during relaxation. Our findings show that carnosine, and its methylated analogues, may have potential therapeutic roles, especially for cardiac function, expanding recent evidence indicating that increased carnosine can protect the heart against ischemia-reperfusion injury [ 41 ].…”

“…This also suggests that the only clear causal link between HCDs and reduced cardiac function shown herein is impaired Ca 2+ handling. Whilst HCDs, and especially carnosine, seem to be protective under conditions of exacerbated oxidative stress [ 41 ], our data indicate that acting as an antioxidant is not a primary physiological role of HCDs in the cardiac muscle.…”

“…Increased muscle carnosine has been associated with improved detoxification of reactive aldehydes via adduct formation [ 12 ]. Interestingly, a role for carnosine in H + buffering and aldehyde detoxification was shown recently in cardiomyocytes under low intracellular pH following ischemia in experimental models where carnosine was increased above physiological levels [ 41 ]. This suggests that, although carnosine may not exert a specific function under normal physiological conditions, it may offer protection under stressful conditions that challenge cellular function and survival.…”

Multiomics reveals the genomic, proteomic and metabolic influences of the histidyl dipeptides on heart

“…In our work, we found that CarnsTg mice exhibit normal cardiac function, and increasing the myocardial production of histidyl dipeptides buffers intracellular pH, facilitates glucose utilization, and attenuates cardiac injury during I/R. 18 Despite this evidence showing histidyl dipeptides imparts cardiac protection, improved glycolysis and influences numerous cellular and signaling pathways, an in-depth understanding of the histidyl dipeptide mediated effects on the genomic, proteomic and metabolomic landscape of the heart has not been performed.…”

Urinary Levels of the Acrolein Conjugates of Carnosine Are Associated with Cardiovascular Disease Risk

“…Carnosine supplementation improves glucose handling [ 8 , 9 ] and renal function [ 10 ] in obese humans or mice and also increases the extrusion of advanced glycation end products (AGEs) [ 11 ]. Other studies suggest carnosine protects against ischemia-reperfusion injury in isolated mouse hearts [ 12 ] and limits atherogenesis in apolipoprotein E null(ApoE-) mice [ 13 ]. Carnosine also limits the deleterious effects of particulate matter exposure on endothelial progenitor cell function in mice [ 14 ].…”