Pyridoxal‐5‐phosphate induced cardioprotection in aging associated with up‐expression of cystathionine‐γ‐lyase, 3‐mercaptopyruvate sulfurtransferase, and ATP‐sensitive potassium channels

Abstract

Background:In the present work, we investigated the cardioprotective potential of pyridoxal-5-phosphate (PLP) in old rats as a cofactor of enzymes that synthesize hydrogen sulphide (H 2 S). Materials and methods:PLP was administered per os in a dose of 0.7 mg per kg daily for 2 weeks. Rats were divided into three groups (adult, old and old +PLP) of 20 animals. The cardiac mRNA levels of genes encoding H 2 S-synthesizing enzymes cystathionine-γ-lyase (CSE) and 3-mercaptopyruvate sulfurtransferase (3-MST), uncoupling proteins (UCP3), subunits of ATP-sensitive potassium (K ATP ) channels were determined using real-time polymerase chain reaction analysis.We also studied the effect of PLP-administration on the content of H 2 S, oxidative stress, the activities of inducible and constitutive NO-synthase (iNOS, cNOS), arginase and nitrate reductase in the heart homogenates as well as cardiac resistance to ischemia-reperfusion in Langendorff-isolated heart model. Results:It was shown that PLP restored mRNA levels of CSE, 3-MST and UCP3 genes, and H 2 S content and also significantly increased the expression of SUR2 and Kir6.1 (2.2 and 3.3 times, respectively) in the heart of old rats. PLP significantly reduced the formation of superoxide, malondialdehyde, diene conjugates as well as the activity of iNOS and arginase. PLP significantly increased constitutive synthesis of NO and prevented reperfusion disturbances of the heart function after ischemia.Conclusions: Thus, PLP-administration in old rats was associated with upexpression of CSE, 3-MST, UCP3 and SUR2 and Kir6.1 subunits of K ATP channels, and also increased cNOS activity and reduced oxidative stress and prevented reperfusion dysfunction of the heart in ischemia-reperfusion. K E Y W O R D Sageing, H 2 S-synthesizing enzymes, ischemia-reperfusion, K ATP channels, pyridoxal-5phosphate

Exercise restores endogenous H2S synthesis and mitochondrial function in the heart of old rats

“…13,14,21 We recently showed that PLP administration in old rats was associated with an increased expression of H 2 S-synthesizing enzymes CSE and 3-MST, increased levels of hydrogen sulphide in the heart tissue, and prevented reperfusion dysfunction of the heart in ischemia-reperfusion. 10 In this study, 3-MST and CSE expression was significantly increased in old exercise-trained rats, and endogenous hydrogen sulphide production in cardiac tissue and cardiac mitochondria was restored to the level of adult untrained animals (Figures 1,2). Similar results with increased expression of 3-MST and CSE and H 2 S levels in old rats during training were obtained by Ma et al 22 The effects of physical training on pore formation in the mitochondria of the heart of old rats were manifested in a decrease in the amplitude of organelle swelling both in calcium-free medium and under the action of the inducer (10 −4 moL/L), as shown in Figure 3B.…”

“…In particular, we have shown the inhibition of mPTP formation in experiments on suspensions mitochondria and the associated reduction in the processes of necrosis and apoptosis in anoxia‐reoxygenation of neonatal cardiomyocytes by pharmacological activators of K ATP channels flocalin and tioflocalin 6,9 . In a series of experiments involving cofactor H 2 S‐synthesizing enzymes pyridoxal‐5‐phosphate and hydrogen sulfide donor NaHS at reduced levels of endogenous H 2 S production in the heart of old rats, we observed increased hydrogen sulfide levels, reduced oxidative stress, and better recovery of function of the ischemic heart during reperfusion that proves the important role of this gaseous transmitter in the regulation of mitochondrial function 5,10 . H 2 S is an important endogenously synthesized signaling molecule synthesized by three enzymes, two of which have a pronounced expression in the cardiovascular system, namely 3‐mercaptopyruvate sulfurtransferase (3‐MST), which is localized mainly in mitochondria, where it functions together with cysteine aminotransferase (CAT) and cystathionine‐γ‐lyase (CSE) in the cytosol of cells 11 .…”

“…6,9 In a series of experiments involving cofactor H 2 S-synthesizing enzymes pyridoxal-5-phosphate and hydrogen sulfide donor NaHS at reduced levels of endogenous H 2 S production in the heart of old rats, we observed increased hydrogen sulfide levels, reduced oxidative stress, and better recovery of function of the ischemic heart during reperfusion that proves the important role of this gaseous transmitter in the regulation of mitochondrial function. 5,10 H 2 S is an important endogenously synthesized signaling molecule synthesized by three enzymes, two of which have a pronounced expression in the cardiovascular system, namely 3-mercaptopyruvate sulfurtransferase (3-MST), which is localized mainly in mitochondria, where it functions together with cysteine aminotransferase (CAT) and cystathionine-γlyase (CSE) in the cytosol of cells. 11 Due to the ability to restore disulphide bonds and sulfhydrogenation of cysteine residues, hydrogen sulphide is able to modify proteins.…”

“…11,12 Disorders of hydrogen sulphide synthesis are associated with such pathologies of the cardiovascular system as hypertension, atherosclerosis and heart failure, 13 the incidence of which increases with age. 14 We recently showed that PLP administration in old rats was associated with up-expression of H 2 S-synthesizing enzymes CSE and 3-MST, reduced oxidative stress and increased cNOS activity, and prevented reperfusion dysfunction of the heart in ischaemia-reperfusion, 10 but we would like to obtain increased H 2 S levels and cardioprotection by the nonpharmacological way. The aim of our work was to study the possible participation of exercise traininginduced regulation of endogenous hydrogen sulphide production in the restoration of mitochondrial function in old rats.…”

Inhibition of the 3-mercaptopyruvate sulfurtransferase—hydrogen sulfide system promotes cellular lipid accumulation

“…Some of the most obvious approaches to achieve this goal may involve exercise—which is known to counteract aging-associated decline in 3-MST mRNA expression in the heart [ 49 ]—or various dietary interventions, including various intermittent fasting or other dietary restriction approaches [ 39 , 46 ]. Betaine, [ 55 ] as well as pyridoxal-5-phosphate [ 56 ], has also been recently shown to upregulate 3-MST expression in the brain and heart of rodents, respectively. There may be also pharmacological possibilities for a redox-based “reactivation” of 3-MST [ 53 , 54 , 57 ].…”