Homocysteine Thiolactone Induces Cardiac Dysfunction: Role of Oxidative Stress

Mendes, Roberta Hack; Sirvente, Raquel; Candido, Georgia Orsi; Mostarda, Cristiano Teixeira; Salemi, Vera Maria Cury; D’Almeida, Vânia; Jacob, Maria; Ribeiro, Maria Flávia Marques; Belló‐Klein, Adriane; Rigatto, Katya; Irigoyen, Maria Cláudia

doi:10.1097/fjc.0b013e3181ce5c28

Cited by 16 publications

(11 citation statements)

References 32 publications

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“…This contrasts with work carried out on rats given homocysteine thiolactone in their water, where diastolic function was compromised [26]. A possible reason for this discrepancy is the acute nature of the current study compared to the longer term of homocysteine treatment in the study by Mendes et al [26]. Also the decrease in the numbers of cells displaying rod shaped morphology in the presence of Hcy with time was no worse than that occurring in the control (Fig.…”

Section: Discussioncontrasting

confidence: 54%

Homocysteine Exposure Impairs Myocardial Resistance to Ischaemia Reperfusion and Oxidative Stress

Almashhadany

Shackebaei

Touw

et al. 2015

Cell Physiol Biochem

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Background/Aims: Hyperhomocysteinaemia is recognised as a strong independent risk factor for developing cardiovascular disease. This study investigated how an acute homocysteine dose affected cardiac performance during ischaemia reperfusion and cardiomyocyte contractility and morphology under normal conditions and during oxidative stress. Methods: Cardiac function was measured in isolated and perfused rat hearts before and after 40 minutes' global normothermic ischaemia. Where used, 0.1 mM L-homocysteine was present prior to, and throughout ischaemia, before wash out after 10 minutes' reperfusion. Calcium transients under normal conditions and changes in contractile synchronicity during oxidative stress (exposure to 0.2 mM H₂O₂) were measured in freshly isolated rat cardiomyocytes incubated for 60 minutes ± 0.1 mM L-homocysteine. Results: During ischaemia reperfusion 0.1 mM L-homocysteine significantly reduced the rate pressure product during reperfusion (10,038 ± 749 vs. 5955 ± 567 mmHg bpm, p < 0.001), but did not affect time to ischaemic contracture. Incubation of freshly isolated cardiomyocytes with 0.1 mM L-homocysteine significantly decreased the amplitude of the calcium transient and slowed the time to half relaxation. Conclusions: These findings suggest that homocysteine exposure affected myocardial recovery from ischaemia and contractile homeostasis although the exact mechanisms for these changes remain to be determined.

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Section: Discussioncontrasting

confidence: 54%

Homocysteine Exposure Impairs Myocardial Resistance to Ischaemia Reperfusion and Oxidative Stress

Almashhadany

Shackebaei

Touw

et al. 2015

Cell Physiol Biochem

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“…This is the first report showing that the increased activity of PON-HCTLase at the level of vitreous may be a protective effect to eliminate HCTL, which mediates endothelial cell dysfunction through N-homocysteinylation of the lysine residues in the proteins (26), while PON-AREase is lowered, probably due to the increased Hcys levels. Vitreous levels of HCTL and PON activities can be markers of diabetic retinopathy.…”

Section: Discussionmentioning

confidence: 84%

Homocysteinethiolactone and Paraoxonase

et al. 2010

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OBJECTIVEParaoxonase (PON) exhibits esterase activity (PON-AREase) and lactonase activity (PON-HCTLase), which prevent LDL oxidation and detoxify homocysteine thiolactone (HCTL). The role of HCTL and PON-HCTLase as a risk factor for the microvascular complication in diabetic retinopathy at the level of vitreous has not been investigated.RESEARCH DESIGN AND METHODSUndiluted vitreous from patients with proliferative diabetic retinopathy (PDR) (n = 13) and macular hole (MH) (n = 8) was used to determine PON-HCTLase and PON-AREase activity spectrophotometrically. HCTL levels were detected by liquid chromatography–tandem mass spectrometry. In vitro studies were done in primary cultures of bovine retinal capillary endothelial cells (BRECs) to determine the dose- and time-dependent effect of HCTL and homocysteine (Hcys) on PON-HCTLase activity, as well as to determine mRNA expression of PON by RT-PCR.RESULTSA significant increase in HCTL and PON-HCTLase activity was observed in PDR compared with MH (P = 0.036, P = 0.001), with a significant positive correlation between them (r = 0.77, P = 0.03). The in vitro studies on BRECs showed a dose- and time-dependent increase in the PON-HCTLase activity and mRNA expression of PON2 when exposed to HCTL and Hcys.CONCLUSIONSThis is the first study showing elevated levels of vitreous HCTL and PON-HCTLase activity in PDR. These elevations are probably a protective effect to eliminate HCTL, which mediates endothelial cell dysfunction. Thus, vitreous levels of HCTL and PON activity can be markers of diabetic retinopathy. The bioinformatics analysis reveals that the structure and function of PON that can be modulated by hyperhomocysteinemia in PDR can affect the dual-enzyme activity of PON.

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“…Moreover, elevated levels of Hcy thiolactone (HTL; an intramolecular thioester of Hcy) were found in response to increasing levels of Hcy as demonstrated in studies involving human cells and animal models [18,19]. Importantly, HTL has been shown to induce oxidative stress [20,21] which has been implicated in several pathologies associated with HHcy [22].…”

Section: Introductionmentioning

confidence: 99%

High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats

et al. 2020

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Background: Both cholesterol (Cho) and methionine (Met, a precursor for homocysteine) are risk factors for fatty liver disease. Since Western diets are rich in Cho and Met, we investigated the hepatic effects of feeding a diet enriched in Met and Cho. Further, based on the reported anti-oxidative and lipid lowering properties of sitagliptin (an antidiabetic drug), we tested whether it could counteract the negative effects of high Cho and Met. We therefore hypothesized that sitagliptin would ameliorate the development of liver pathology that is produced by feeding diets rich in either Cho, Met, or both. Methods: Male Sprague Dawley rats were fed ad libitum a) control diet, or b) high Met or c) high Cho, or d) high Met + high Cho diets for 35 days. From day 10 to 35, 50% of rats in each dietary group were gavaged with either vehicle or an aqueous suspension of sitagliptin (100 mg/kg/day). Liver samples were harvested for histological, molecular, and biochemical analyses. Results: The high Cho diet produced significant hepatic steatosis which was unaffected by sitagliptin. Contrary to expectation, sitagliptin exacerbated expression of hepatic markers of oxidative stress and fibrosis in rats fed high Cho. Corresponding increases in 4-hydroxynonenal adducts and collagen deposition were demonstrated by immunohistochemistry and sirius red staining. These hepatic changes were absent in rats on the high Met diet and they were comparable to controls. The inclusion of Met in the high Cho diet resulted in significant reduction of the hepatic steatosis, oxidative stress, and fibrosis produced by high Cho alone. Conclusion: Sitagliptin exacerbated the effects of high Cho on both oxidative stress and fibrosis, resulting in NASH like symptoms that were significantly reversed by the inclusion of Met.

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Homocysteine Thiolactone Induces Cardiac Dysfunction: Role of Oxidative Stress

Cited by 16 publications

References 32 publications

Homocysteine Exposure Impairs Myocardial Resistance to Ischaemia Reperfusion and Oxidative Stress

Homocysteine Exposure Impairs Myocardial Resistance to Ischaemia Reperfusion and Oxidative Stress

Homocysteinethiolactone and Paraoxonase

High levels of dietary methionine improves sitagliptin-induced hepatotoxicity by attenuating oxidative stress in hypercholesterolemic rats

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