Vol 60, No 2 (2022)
Original paper
Published online: 2022-05-30
A chronic moderate methionine administration induced hyperhomocysteinemia associated with cardiovascular disease phenotype in the sand rat Psammomys obesus
Abstract
Introduction. Cardiovascular diseases were defined as coronary artery, cerebrovascular, or peripheral arterial disease. Hyperhomocysteinemia (Hhcy) is an independent risk factor of cardiovascular diseases, including atherosclerosis. Our previous studies demonstrated the involvement of Hhcy in cardiovascular remodeling in the sand rat Psammomys obesus. Material and methods. An experimental Hhcy was induced, in the sand rat Psammomys obesus, by a daily intraperitoneal injection of 70 mg/kg of methionine for a total duration of 6 months. The impact of Hhcy on the cellular and matrix structures of the heart, aorta and liver was analyzed using histological techniques. Additionally we treatedprimary cultures of aortic smooth muscle cells (SMCs) with high concentration of methionine to investigate the effects of methionine at the cellular level. Results. A moderate Hhcy induced a significant increase in the extracellular matrix components particularly collagens which accumulated in the interstitial and perivascular spaces in the studied organs indicating a developing fibrosis. A liver steatosis was also observed following methionine treatment. Further analysis of the aorta showed that Hhcy also induced vascular alterations including SMCs reorientation and proliferation associated with aneurysm formation. Conclusions. Our results show for the first time that Hhcy can induce a cardiovascular and liver diseases phenotype in Psammomys obesus, a species previously shown to be a good model for the studies of diabetes and other metabolism-related pathologies.
Keywords: Cardiovascular diseasesHyperhomocysteinemiaLiverMethioninePsammomys obesusSMCs
References
- Rabinovich-Nikitin I, Lieberman B, Martino TA, et al. Circadian-Regulated Cell Death in Cardiovascular Diseases. Circulation. 2019; 139(7): 965–980.
- Guilland JC, Favier A, Courcy GP, et al. L’hyperhomocystéinémie : facteur de risque cardiovasculaire ou simple marqueur ? Pathologie Biologie. 2003; 51(2): 101–110.
- Chaturvedi P, Kamat PK, Kalani A, et al. High Methionine Diet Poses Cardiac Threat: A Molecular Insight. J Cell Physiol. 2016; 231(7): 1554–1561.
- Yefsah-Idres A, Benazzoug Y, Otman A, et al. Hepatoprotective effects of lycopene on liver enzymes involved in methionine and xenobiotic metabolism in hyperhomocysteinemic rats. Food Funct. 2016; 7(6): 2862–2869.
- Stojanović M, Todorović D, Šćepanović Lj, et al. Subchronic methionine load induces oxidative stress and provokes biochemical and histological changes in the rat liver tissue. Mol Cell Biochem. 2018; 448(1-2): 43–50.
- Gibson JB, Carson NA, Neill DW. Pathological findings in homocystinuria. J Clin Pathol. 1964; 17: 427–437.
- Yang F, Tan HM, Wang H. Hyperhomocysteinemia and atherosclerosis - An overview. Int J Pharma Bio Sci. 2011; 2: 348–354.
- Maron BA, Loscalzo J. The treatment of hyperhomocysteinemia. Annu Rev Med. 2009; 60: 39–54.
- Roblin X, Pofelski J, Zarski JP. Rôle de l’homocystéine au cours de la stéatose hépatique et de l’hépatite chronique C. Gastroentérologie Clinique et Biologique. 2007; 31(4): 415–420.
- Baszczuk A, Kopczyński Z. Hyperhomocysteinemia in patients with cardiovascular disease. Postepy Hig Med Dosw (Online). 2014; 68: 579–589.
- Hamlat N, Negazzi S, Forcheron F, et al. Lipogenesis in arterial wall and vascular smooth muscle cells of Psammomys obesus: its regulation and abnormalities in diabetes. Diabetes Metab. 2010; 36(3): 221–228.
- Berdja S, Smail L, Saka B, et al. Glucotoxicity induced oxidative stress and inflammation in vivo and in vitro in psammomys obesus: involvement of aqueous extract of brassica rapa rapifera. Evid Based Complement Alternat Med. 2016; 2016: 3689208.
- Chaouad B, Moudilou EN, Ghoul A, et al. Hyperhomocysteinemia and myocardial remodeling in the sand rat, Psammomys obesus. Acta Histochem. 2019; 121(7): 823–832.
- Daly M, Daly S. On the feeding ecology of psammomys obesus (rodentia, gerbillidae) in the wadi saoura, algeria. Mammalia. 1973; 37(4).
- Aouichat Bouguerra S, Benazzoug Y, Bekkhoucha F, et al. Effect of high glucose concentration on collagen synthesis and cholesterol level in the phenotypic modulation of aortic cultured smooth muscle cells of sand rat (Psammomys obesus). Exp Diabesity Res. 2004; 5(3): 227–235.
- Frantzen F, Faaren AL, Alfheim I, et al. Enzyme conversion immunoassay for determining total homocysteine in plasma or serum. Clin Chem. 1998; 44(2): 311–316.
- Kawakami K, Tsukada A, Okubo M, et al. A rapid electrophoretic method for the detection of serum Lp(a) lipoprotein. Clin Chim Acta. 1989; 185(2): 147–155.
- Martoja R, Martoja M. Initiation aux techniques de l’histologie animale. Paris: Masson. ; 1967.
- Bouguerra SA, Bourdillon MC, Dahmani Y, et al. Non insulin dependent diabetes in sand rat (Psammomys obesus) and production of collagen in cultured aortic smooth muscle cells. influence of insulin. Int J Exp Diabetes Res. 2001; 2(1): 37–46.
- Benavides MA, Oelschlager DK, Zhang HG, et al. Methionine inhibits cellular growth dependent on the p53 status of cells. Am J Surg. 2007; 193(2): 274–283.
- Hildebrandt S, Steinhart H, Paschke A, et al. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976; 72(3): 248–254.
- Park CM, Cho CW, Rosenfeld ME, et al. Methionine supplementation accelerates oxidative stress and nuclear factor kappaB activation in livers of C57BL/6 mice. J Med Food. 2008; 11(4): 667–674.
- Steed MM, Tyagi SC. Mechanisms of Cardiovascular Remodeling in Hyperhomocysteinemia. Antioxid Redox Signal. 2011; 15(7): 1927–1943.
- Miller A, Mujumdar V, Shek E, et al. Hyperhomocyst(e)inemia induces multiorgan damage. Heart Vessels. 2000; 15(3): 135–143.
- Akasaka K, Akasaka N, Di Luozzo G, et al. Homocysteine promotes p38-dependent chemotaxis in bovine aortic smooth muscle cells. J Vasc Surg. 2005; 41(3): 517–522.
- Sharma M, Rai SK, Tiwari M, et al. Effect of hyperhomocysteinemia on cardiovascular risk factors and initiation of atherosclerosis in Wistar rats. Eur J Pharmacol. 2007; 574(1): 49–60.
- Kirac D, Negis Y, Ozer NK. Vitamin E attenuates homocysteine and cholesterol induced damage in rat aorta. Cardiovasc Pathol. 2013; 22(6): 465–472.
- Bellamy MF, McDowell IF, Ramsey MW, et al. Hyperhomocysteinemia after an oral methionine load acutely impairs endothelial function in healthy adults. Circulation. 1998; 98(18): 1848–1852.
- Charpiot P, Bescond A, Augier T, et al. Hyperhomocysteinemia induces elastolysis in minipig arteries: structural consequences, arterial site specificity and effect of captopril-hydrochlorothiazide. Matrix Biol. 1998; 17(8-9): 559–574.
- Hidiroglou N, Gilani GS, Long L, et al. The influence of dietary vitamin E, fat, and methionine on blood cholesterol profile, homocysteine levels, and oxidizability of low density lipoprotein in the gerbil. J Nutr Biochem. 2004; 15(12): 730–740.
- Raaf L, Noll C, Cherifi ME, et al. Myocardial fibrosis and TGFB expression in hyperhomocysteinemic rats. Mol Cell Biochem. 2011; 347(1-2): 63–70.
- Ghoul A, Moudilou E, Cherifi ME, et al. The role of homocysteine in seminal vesicles remodeling in rat. Folia Histochem Cytobiol. 2017; 55(2): 62–73.
- Zhou J, Møller J, Danielsen CC, et al. Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2001; 21(9): 1470–1476.
- Liao D, Tan H, Hui R, et al. Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance. Circ Res. 2006; 99(6): 598–606.
- Aasvee K, Jauhiainen M, Kurvinen E, et al. Determinants of risk factors of atherosclerosis in the postinfarction period: the Tallinn MI study. Scand J Clin Lab Invest. 2006; 66(3): 191–199.
- Au-Yeung KKW, Woo CWH, Sung FL, et al. Hyperhomocysteinemia activates nuclear factor-kappaB in endothelial cells via oxidative stress. Circ Res. 2004; 94(1): 28–36.
- Lazzerini PE, Capecchi PL, Selvi E, et al. Hyperhomocysteinemia, inflammation and autoimmunity. Autoimmun Rev. 2007; 6(7): 503–509.
- Joseph J, Washington A, Joseph L, et al. Hyperhomocysteinemia leads to adverse cardiac remodeling in hypertensive rats. Am J Physiol Heart Circ Physiol. 2002; 283(6): H2567–H2574.
- Matté C, Stefanello FM, Mackedanz V, et al. Homocysteine induces oxidative stress, inflammatory infiltration, fibrosis and reduces glycogen/glycoprotein content in liver of rats. Int J Dev Neurosci. 2009; 27(4): 337–344.
- Devi S, Kennedy RH, Joseph L, et al. Effect of long-term hyperhomocysteinemia on myocardial structure and function in hypertensive rats. Cardiovasc Pathol. 2006; 15(2): 75–82.
- Othmani Mecif K, Aouichat Bouguerra S, Benazzoug Y. Plasma and aorta biochemistry and mmps activities in female rabbit fed methionine enriched diet and their offspring. J Nutr Metab. 2017; 2017: 2785142.
- Balcioğlu AS, Durakoğlugil ME, Ciçek D, et al. Epicardial adipose tissue thickness and plasma homocysteine in patients with metabolic syndrome and normal coronary arteries. Diabetol Metab Syndr. 2014; 6: 62.
- Wang G, Woo CWH, Sung FL, et al. Increased monocyte adhesion to aortic endothelium in rats with hyperhomocysteinemia: role of chemokine and adhesion molecules. Arterioscler Thromb Vasc Biol. 2002; 22(11): 1777–1783.
- Zhang R, Ma J, Xia M, et al. Mild hyperhomocysteinemia induced by feeding rats diets rich in methionine or deficient in folate promotes early atherosclerotic inflammatory processes. J Nutr. 2004; 134(4): 825–830.
- Dayal S, Wilson KM, Leo L, et al. Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia. Blood. 2006; 108(7): 2237–2243.
- Postea O, Krotz F, Henger A, et al. Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine. Arterioscler Thromb Vasc Biol. 2006; 26(3): 508–513.
- Charpiot P, Bescond A, Augier T, et al. Medial elastic structure alterations in atherosclerotic arteries in minipigs: plaque proximity and arterial site specificity. Matrix Biol. 1997; 15(7): 455–467.
- Chaussalet M, Lamy E, Foucault-Bertaud A, et al. Homocysteine modulates the proteolytic potential of human vascular endothelial cells. Biochem Biophys Res Commun. 2004; 316(1): 170–176.
- Bennett MR, Sinha S, Owens GK. Vascular smooth muscle cells in atherosclerosis. Circ Res. 2016; 118(4): 692–702.
- Tyagi SC. Homocysteine redox receptor and regulation of extracellular matrix components in vascular cells. Am J Physiol. 1998; 274(2): C396–C405.
- Tsai JC, Wang H, Perrella MA, et al. Induction of cyclin A gene expression by homocysteine in vascular smooth muscle cells. J Clin Invest. 1996; 97(1): 146–153.
- Murthy SN, Obregon DF, Chattergoon NN, et al. Rosiglitazone reduces serum homocysteine levels, smooth muscle proliferation, and intimal hyperplasia in Sprague-Dawley rats fed a high methionine diet. Metabolism. 2005; 54(5): 645–652.
- Yao D, Sun NL. Hyperhomocysteinemia accelerates collagen accumulation in the adventitia of balloon-injured rat carotid arteries via angiotensin II type 1 receptor. Int J Mol Sci. 2014; 15(11): 19487–19498.
- Liu Z, Luo H, Zhang Lu, et al. Hyperhomocysteinemia exaggerates adventitial inflammation and angiotensin II-induced abdominal aortic aneurysm in mice. Circ Res. 2012; 111(10): 1261–1273.
- Škovierová H, Vidomanová E, Mahmood S, et al. The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci. 2016; 17(10).
- Dai Y, Zhu J, Meng Di, et al. Association of homocysteine level with biopsy-proven non-alcoholic fatty liver disease: a meta-analysis. J Clin Biochem Nutr. 2016; 58(1): 76–83.
- Ai Y, Sun Z, Peng C, et al. Homocysteine induces hepatic steatosis involving ER stress response in high methionine diet-fed mice. Nutrients. 2017; 9(4).
- Robert K, Chassé JF, Santiard-Baron D, et al. Altered gene expression in liver from a murine model of hyperhomocysteinemia. J Biol Chem. 2003; 278(34): 31504–31511.
- Luo X, Xiao L, Yang H, et al. Homocysteine downregulates gene expression of heme oxygenase-1 in hepatocytes. Nutr Metab (Lond). 2014; 11(1): 55.
- Lynch SM, Strain JJ. Increased hepatic lipid peroxidation with methionine toxicity in the rat. Free Radic Res Commun. 1989; 5(4-5): 221–226.
- Mori N, Hirayama K. Long-term consumption of a methionine-supplemented diet increases iron and lipid peroxide levels in rat liver. J Nutr. 2000; 130(9): 2349–2355.
- Tamanna N, Kroeker K, Braun K, et al. The effect of short-term methionine restriction on glutathione synthetic capacity and antioxidant responses at the whole tissue and mitochondrial level in the rat liver. Exp Gerontol. 2019; 127: 110712.
