Amino Acid Regulation in Metabolic Heart Disease: Mechanisms and Therapeutic Potential

Yingying Lu , Bin Li , Nadine Mbabazi , Khan Musawir Abbas , Pengqi Lin , Huanan Pei , Yifan Bao , Lina Zou , Feng Gao , Feiyan Yang , Yu Bai , Dechun Yin

Cardiovascular Innovations and Applications ›› 2026, Vol. 11 ›› Issue (1) : 988

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Cardiovascular Innovations and Applications ›› 2026, Vol. 11 ›› Issue (1) :988 DOI: 10.15212/CVIA.2025.0032
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Amino Acid Regulation in Metabolic Heart Disease: Mechanisms and Therapeutic Potential
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Abstract

In normal cardiac energy metabolism, 95% of the heart’s energy is provided by mitochondria, and preferences for energy-providing substrates vary at different times (Nguyen BY, Ruiz-Velasco A, Bui T, Collins L, Wang X, Liu W. Mitochondrial function in the heart: the insight into mechanisms and therapeutic potentials. Br J Pharmacol 2019;176(22):4302-4318). However, prolonged metabolic alterations impair cardiac function (Hu L, Tang D, Qi B, Guo D, Wang Y, Geng J, et al. Mfn2/Hsc70 complex mediates the formation of mitochondria-lipid droplets membrane contact and regulates myocardial lipid metabolism. Adv Sci (Weinh) 2024;11(14):e2307749). Therefore, this study primarily focuses on the relationship between amino acid metabolism and diabetic cardiomyopathy and atherosclerosis. Changes in metabolic processes also promote the development and worsening of these two diseases. Lipid and glucose metabolism in such diseases have been extensively studied, and emerging evidence suggests that amino acid metabolism also plays major roles in diabetic cardiomyopathy and atherosclerosis. Specific amino acid intake or catabolism might influence oxidative stress, inflammation, and fibrosis, among related processes, thus indirectly highlighting their potential as novel targets for metabolic interventions. However, the mechanisms and clinical relevance of amino acid metabolism in these diseases remain incompletely understood and warrant further investigation.

Keywords

diabetic cardiomyopathy / atherosclerosis / amino acids / metabolism

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Yingying Lu, Bin Li, Nadine Mbabazi, Khan Musawir Abbas, Pengqi Lin, Huanan Pei, Yifan Bao, Lina Zou, Feng Gao, Feiyan Yang, Yu Bai, Dechun Yin. Amino Acid Regulation in Metabolic Heart Disease: Mechanisms and Therapeutic Potential. Cardiovascular Innovations and Applications, 2026, 11 (1) : 988 DOI:10.15212/CVIA.2025.0032

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References

[1]

Roe ND, He EY, Wu Z, Ren J. Folic acid reverses nitric oxide synthase uncoupling and prevents cardiac dysfunction in insulin resistance: role of Ca2+/calmodulin-activated protein kinase II. Free Radic Biol Med. 2013. Vol. 65:234-43

[2]

Forzisi E, Yu W, Rajwade P, Sesti F. Antagonistic roles of Ras-MAPK and Akt signaling in integrin-K+ channel complex-mediated cellular apoptosis. FASEB J. 2022. Vol. 36(5):e22292

[3]

Frendo-Cumbo S, Tokarz VL, Bilan PJ, Brumell JH, Klip A. Communication between autophagy and insulin action: at the crux of insulin action-insulin resistance? Front Cell Dev Biol. 2021. Vol. 9:708431

[4]

Han K, Jia N, Zhong Y, Shang X. S14G-humanin alleviates insulin resistance and increases autophagy in neurons of APP/PS 1 transgenic mouse. J Cell Biochem. 2018. Vol. 119(4):3111-7

[5]

Peyter AC, Armengaud JB, Guillot E, Yzydorczyk C. Endothelial progenitor cells dysfunctions and cardiometabolic disorders: from mechanisms to therapeutic approaches. Int J Mol Sci. 2021. Vol. 22(13):6667

[6]

Gawlowski T, Suarez J, Scott B, Torres-Gonzalez M, Wang H, Schwappacher R, et al.. Modulation of dynamin-related protein 1 (DRP1) function by increased O-linked-β-N-acetylglucosamine modification (O-GlcNAc) in cardiac myocytes. J Biol Chem. 2012. Vol. 287(35):30024-34

[7]

Cao H, Hu Y, Zhu X, Yao N, Gu J, Wang Y, et al.. O-GlcNAc transferase affects the signal transduction of β1 adrenoceptor in adult rat cardiomyocytes by increasing the O-GlcNAcylation of β1 adrenoceptor. Biochem Biophys Res Commun. 2020. Vol. 528(1):71-7

[8]

Kronlage M, Dewenter M, Grosso J, Fleming T, Oehl U, Lehmann LH, et al.. O-GlcNAcylation of histone deacetylase 4 protects the diabetic heart from failure. Circulation. 2019. Vol. 140(7):580-94

[9]

Lehmann LH, Jebessa ZH, Kreusser MM, Horsch A, He T, Kronlage M, et al.. A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat Med. 2018. Vol. 24(1):62-72

[10]

Gimbrone MA Jr, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res. 2016. Vol. 118(4):620-36

[11]

Gao L, Zhao Y, Wu H, Lin X, Guo F, Li J, et al.. Polycystic ovary syndrome fuels cardiovascular inflammation and aggravates ischemic cardiac injury. Circulation. 2023. Vol. 148(24):1958-73

[12]

Proto JD, Doran AC, Gusarova G, Yurdagul A Jr, Sozen E, Subramanian M, et al.. Regulatory T cells promote macrophage efferocytosis during inflammation resolution. Immunity. 2018. Vol. 49(4):666-77.e6

[13]

Roy P, Orecchioni M, Ley K. How the immune system shapes atherosclerosis: roles of innate and adaptive immunity. Nat Rev Immunol. 2022. Vol. 22(4):251-65

[14]

Sage AP, Tsiantoulas D, Binder CJ, Mallat Z. The role of B cells in atherosclerosis. Nat Rev Cardiol. 2019. Vol. 16(3):180-96

[15]

Grootaert MOJ, Finigan A, Figg NL, Uryga AK, Bennett MR. SIRT6 protects smooth muscle cells from senescence and reduces atherosclerosis. Circ Res. 2021. Vol. 128(4):474-91

[16]

Kotla S, Vu HT, Ko KA, Wang Y, Imanishi M, Heo KS, et al.. Endothelial senescence is induced by phosphorylation and nuclear export of telomeric repeat binding factor 2-interacting protein. JCI Insight. 2019. Vol. 4(9):e124867

[17]

Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol. 2021. Vol. 22(2):119-41

[18]

Doestzada M, Zhernakova DV, van den Munckhof ICL, Wang D, Kurilshikov A, Chen L, et al.. Systematic analysis of relationships between plasma branched-chain amino acid concentrations and cardiometabolic parameters: an association and Mendelian randomization study. BMC Med. 2022. Vol. 20(1):485

[19]

Lotta LA, Scott RA, Sharp SJ, Burgess S, Luan J, Tillin T, et al.. Genetic predisposition to an impaired metabolism of the branched-chain amino acids and risk of type 2 diabetes: a Mendelian randomisation analysis. PLoS Med. 2016. Vol. 13(11):e1002179

[20]

Zhao H, Zhang F, Sun D, Wang X, Zhang X, Zhang J, et al.. Branched-chain amino acids exacerbate obesity-related hepatic glucose and lipid metabolic disorders via attenuating Akt2 signaling. Diabetes. 2020. Vol. 69(6):1164-77

[21]

Cifarelli V, Beeman SC, Smith GI, Yoshino J, Morozov D, Beals JW, et al.. Decreased adipose tissue oxygenation associates with insulin resistance in individuals with obesity. J Clin Invest. 2020. Vol. 130(12):6688-99

[22]

Zhao Y, Gao L, Chen J, Wei J, Lin G, Hu K, et al.. Remote limb ischemic conditioning alleviates steatohepatitis via extracellular vesicle-mediated muscle-liver crosstalk. Cell Metabolism. 2025. Vol. 37(4):886-902.e7

[23]

Mahendran Y, Jonsson A, Have CT, Allin KH, Witte DR, Jørgensen ME, et al.. Genetic evidence of a causal effect of insulin resistance on branched-chain amino acid levels. Diabetologia. 2017. Vol. 60(5):873-8

[24]

Abdualkader AM, Karwi QG, Lopaschuk GD, Al Batran R. The role of branched-chain amino acids and their downstream metabolites in mediating insulin resistance. J Pharm Pharm Sci. 2024. Vol. 27:13040

[25]

Uddin GM, Karwi QG, Pherwani S, Gopal K, Wagg CS, Biswas D, et al.. Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart. Metabolism. 2021. Vol. 124:154871

[26]

Lee J, Vijayakumar A, White PJ, Xu Y, Ilkayeva O, Lynch CJ, et al.. BCAA supplementation in mice with diet-induced obesity alters the metabolome without impairing glucose homeostasis. Endocrinology. 2021. Vol. 162(7):bqab062

[27]

Li T, Zhang Z, Kolwicz SC Jr, Abell L, Roe ND, Kim M, et al.. Defective branched-chain amino acid catabolism disrupts glucose metabolism and sensitizes the heart to ischemia-reperfusion injury. Cell Metab. 2017. Vol. 25(2):374-85

[28]

Shao D, Villet O, Zhang Z, Choi SW, Yan J, Ritterhoff J, et al.. Glucose promotes cell growth by suppressing branched-chain amino acid degradation. Nat Commun. 2018. Vol. 9(1):2935

[29]

Lu QB, Fu X, Liu Y, Wang ZC, Liu SY, Li YC, et al.. Disrupted cardiac fibroblast BCAA catabolism contributes to diabetic cardiomyopathy via a periostin/NAP1L2/SIRT3 axis. Cell Mol Biol Lett. 2023. Vol. 28(1):93

[30]

Sun Y, Sun B, Wang Z, Lv Y, Ma Q. Short-term decreasing and increasing dietary BCAA have similar, but not identical effects on lipid and glucose metabolism in lean mice. Int J Mol Sci. 2023. Vol. 24(6):5401

[31]

Yang Y, Zhao M, He X, Wu Q, Li DL, Zang WJ. Pyridostigmine protects against diabetic cardiomyopathy by regulating vagal activity, gut microbiota, and branched-chain amino acid catabolism in diabetic mice. Front Pharmacol. 2021. Vol. 12:647481

[32]

Cummings NE, Williams EM, Kasza I, Konon EN, Schaid MD, Schmidt BA, et al.. Restoration of metabolic health by decreased consumption of branched-chain amino acids. J Physiol. 2018. Vol. 596(4):623-45

[33]

Glynn EL, Piner LW, Huffman KM, Slentz CA, Elliot-Penry L, AbouAssi H, et al.. Impact of combined resistance and aerobic exercise training on branched-chain amino acid turnover, glycine metabolism and insulin sensitivity in overweight humans. Diabetologia. 2015. Vol. 58(10):2324-35

[34]

Zhou M, Shao J, Wu CY, Shu L, Dong W, Liu Y, et al.. Targeting BCAA catabolism to treat obesity-associated insulin resistance. Diabetes. 2019. Vol. 68(9):1730-46

[35]

Zhang C, Wang S, Wu Y, Guo Y, Wang X. Baseline serum BCAAs are related to the improvement in insulin resistance in obese people after a weight loss intervention. Diabetes Metab Syndr Obes. 2023. Vol. 16:179-86

[36]

Ren W, Xia Y, Chen S, Wu G, Bazer FW, Zhou B, et al.. Glutamine metabolism in macrophages: a novel target for obesity/type 2 diabetes. Adv Nutr. 2019. Vol. 10(2):321-30

[37]

Sun Y, Gao HY, Fan ZY, He Y, Yan YX. Metabolomics signatures in type 2 diabetes: a systematic review and integrative analysis. J Clin Endocrinol Metab. 2020. Vol. 105(4):dgz240

[38]

Torres-Santiago L, Mauras N, Hossain J, Weltman AL, Darmaun D. Does oral glutamine improve insulin sensitivity in adolescents with type 1 diabetes? Nutrition. 2017. Vol. 34:1-6

[39]

Tsai PH, Liu JJ, Chiu WC, Pai MH, Yeh SL. Effects of dietary glutamine on adhesion molecule expression and oxidative stress in mice with streptozotocin-induced type 1 diabetes. Clin Nutr. 2011. Vol. 30(1):124-9

[40]

Badole SL, Jangam GB, Chaudhari SM, Ghule AE, Zanwar AA.L-glutamine supplementation prevents the development of experimental diabetic cardiomyopathy in streptozotocin-nicotinamide induced diabetic rats. PloS One. 2014. Vol. 9(3):e92697

[41]

Zhang H, Cui YC, Li K, Yang BQ, Liu XP, Zhang D, et al.. Glutamine protects cardiomyocytes from hypoxia/reoxygenation injury under high glucose conditions through inhibition of the transforming growth factor-β1-Smad 3 pathway. Arch Biochem Biophys. 2016. Vol. 596:43-50

[42]

Ugurlucan M, Erer D, Karatepe O, Ziyade S, Haholu A, Gungor Ugur-lucan F, et al.. Glutamine enhances the heat shock protein 70 expression as a cardioprotective mechanism in left heart tissues in the presence of diabetes mellitus. Expert Opin Ther Targets. 2010. Vol. 14(11):1143-56

[43]

Kennel PJ, Liao X, Saha A, Ji R, Zhang X, Castillero E, et al.. Impairment of myocardial glutamine homeostasis induced by suppression of the amino acid carrier SLC1A 5 in failing myocardium. Circ Heart Fail. 2019. Vol. 12(12):e006336

[44]

Groening P, Huang Z, La Gamma EF, Levy RJ. Glutamine restores myocardial cytochrome C oxidase activity and improves cardiac function during experimental sepsis. J Parenter Enteral Nutr. 2011. Vol. 35(2):249-54

[45]

Sufit A, Weitzel LB, Hamiel C, Queensland K, Dauber I, Rooyackers O, et al.. Pharmacologically dosed oral glutamine reduces myocardial injury in patients undergoing cardiac surgery: a randomized pilot feasibility trial. J Parenter Enteral Nutr. 2012. Vol. 36(5):556-61

[46]

Safi SZ, Batumalaie K, Mansor M, Chinna K, Mohan S, Karimian H, et al.. Glutamine treatment attenuates hyperglycemia-induced mitochondrial stress and apoptosis in umbilical vein endothelial cells. Clinics (Sao Paulo). 2015. Vol. 70(8):569-76

[47]

Nasri M, Adibhesami G, Mahdavifard S, Babaeenezhad E, Ahmadvand H. Exogenous glutamine ameliorates diabetic nephropathy in a rat model of type 2 diabetes mellitus through its antioxidant and anti-inflammatory activities. Arch Physiol Biochem. 2023. Vol. 129(2):363-72

[48]

Han G, Takahashi H, Murao N, Gheni G, Yokoi N, Hamamoto Y, et al.. Glutamate is an essential mediator in glutamine-amplified insulin secretion. J Diabetes Investig. 2021. Vol. 12(6):920-30

[49]

Modi H, Cornu M, Thorens B. Glutamine stimulates biosynthesis and secretion of insulin-like growth factor 2 (IGF2), an autocrine regulator of beta cell mass and function. J Biol Chem. 2014. Vol. 289(46):31972-82

[50]

Krone MJ, Rivera CN, Rivera ME, Watne RM, Lemonds SE, Wommack AJ, et al.. Excess glutamine does not alter myotube metabolism or insulin sensitivity. Amino Acids. 2022. Vol. 54(3):455-68

[51]

Ezeonwumelu IJ, Mode AM, Magaji UF, Nzoniwu NA, Tangaza MH, Tanimu FI, et al.. Coadministration of L-alanine and L-glutamine ameliorate blood glucose levels, biochemical indices and histological features in alloxan-induced diabetic rats. J Food Biochem. 2022. Vol. 46(12):e14420

[52]

da Purificação NRC, Garcia VB, Frez FCV, Sehaber CC, Lima KRA, de Oliveira Lima MF, et al.. Combined use of systemic quercetin, glutamine and alpha-tocopherol attenuates myocardial fibrosis in diabetic rats. Biomed Pharmacother. 2022. Vol. 151:113131

[53]

Abboud KY, Reis SK, Martelli ME, Zordão OP, Tannihão F, de Souza AZZ, et al.. Oral glutamine supplementation reduces obesity, pro-inflammatory markers, and improves insulin sensitivity in DIO Wistar rats and reduces waist circumference in overweight and obese humans. Nutrients. 2019. Vol. 11(3):536

[54]

Pitaloka DMI, Ko CH, Lin MT, Yeh SL, Yeh CL. Glutamine administration promotes hepatic glucose homeostasis through regulating the PI3K/Akt pathway in high-fat diet-induced obese mice with limb ischemia. Nutr Res. 2019. Vol. 68:45-53

[55]

Salabei JK, Lorkiewicz PK, Holden CR, Li Q, Hong KU, Bolli R, et al.. Glutamine regulates cardiac progenitor cell metabolism and proliferation. Stem Cells. 2015. Vol. 33(8):2613-27

[56]

Mansour A, Mohajeri-Tehrani MR, Qorbani M, Heshmat R, Larijani B, Hosseini S. Effect of glutamine supplementation on cardiovascular risk factors in patients with type 2 diabetes. Nutrition. 2015. Vol. 31(1):119-26

[57]

Samocha-Bonet D, Chisholm DJ, Gribble FM, Coster ACF, Carpenter KH, Jones GRD, et al.. Glycemic effects and safety of L-glutamine supplementation with or without sitagliptin in type 2 diabetes patients-a randomized study. PloS One. 2014. Vol. 9(11):e113366

[58]

Grintescu IM, Luca Vasiliu I, Cucereanu Badica I, Mirea L, Pavelescu D, Balanescu A, et al.. The influence of parenteral glutamine supplementation on glucose homeostasis in critically ill polytrauma patients-a randomized-controlled clinical study. Clin Nutr. 2015. Vol. 34(3):377-82

[59]

Ishinoda Y, Masaki N, Hitomi Y, Taruoka A, Kawai A, Iwashita M, et al.. A low arginine/ornithine ratio is associated with long-term cardiovascular mortality. J Atheroscler Thromb. 2023. Vol. 30(10):1364-75

[60]

Clarkson P, Adams MR, Powe AJ, Donald AE, McCredie R, Robinson J, et al.. Oral L-arginine improves endothelium-dependent dilation in hypercholesterolemic young adults. J Clin Invest. 1996. Vol. 97(8):1989-94

[61]

Böger RH, Bode-Böger SM, Phivthong-ngam L, Brandes RP, Schwedhelm E, Mügge A, et al.. Dietary L-arginine and α-tocopherol reduce vascular oxidative stress and preserve endothelial function in hypercholesterolemic rabbits via different mechanisms. Atherosclerosis. 1998. Vol. 141(1):31-43

[62]

Suzuki T, Hayase M, Hibi K, Hosokawa H, Yokoya K, Fitzgerald PJ, et al.. Effect of local delivery of L-arginine on in-stent restenosis in humans. Am J Cardiol. 2002. Vol. 89(4):363-7

[63]

Durante W, Johnson FK, Johnson RA. Arginase: a critical regulator of nitric oxide synthesis and vascular function. Clin Exp Pharmacol Physiol. 2007. Vol. 34(9):906-11

[64]

Morris SM. Arginine metabolism in vascular biology and disease. Vasc Med. 2005. 10 Suppl 1:S83-7

[65]

Chicoine LG, Paffett ML, Young TL, Nelin LD. Arginase inhibition increases nitric oxide production in bovine pulmonary arterial endothelial cells. Am J Physiol Lung Cell Mol Physiol. 2004. Vol. 287(1):L60-8

[66]

Nelin LD, Wang X, Zhao Q, Chicoine LG, Young TL, Hatch DM, et al.. MKP-1 switches arginine metabolism from nitric oxide synthase to arginase following endotoxin challenge. Am J Physiol Cell Physiol. 2007. Vol. 293(2):C632-40

[67]

Morris CR, Kato GJ, Poljakovic M, Wang X, Blackwelder WC, Sachdev V, et al.. Dysregulated arginine metabolism, hemolysis-associated pulmonary hypertension, and mortality in sickle cell disease. J Am Med Assoc. 2005. Vol. 294(1):81-90

[68]

Ming XF, Barandier C, Viswam-bharan H, Kwak BR, Mach F, Mazzolai L, et al.. Thrombin stimulates human endothelial arginase enzymatic activity via RhoA/ROCK pathway: implications for atherosclerotic endothelial dysfunction. Circulation. 2004. Vol. 110(24):3708-14

[69]

Ryoo S, Gupta G, Benjo A, Lim HK, Camara A, Sikka G, et al.. Endothelial arginase II: a novel target for the treatment of atherosclerosis. Circ Res. 2008. Vol. 102(8):923-32

[70]

Erdely A, Kepka-Lenhart D, Salmen-Muniz R, Chapman R, Hulderman T, Kashon M, et al.. Arginase activities and global arginine bioavailability in wild-type and ApoE-deficient mice: responses to high fat and high cholesterol diets. PLoS One. 2010. Vol. 5(12):e15253

[71]

Hayashi T, Esaki T, Sumi D, Mukherjee T, Iguchi A, Chaudhuri G. Modulating role of estradiol on arginase II expression in hyperlipidemic rabbits as an atheroprotective mechanism. Proc Natl Acad Sci U S A. 2006. Vol. 103(27):10485-90

[72]

Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata M. Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A. 1995. Vol. 92(18):8264-8

[73]

Corraliza IM, Soler G, Eichmann K, Modolell M. Arginase induction by suppressors of nitric oxide synthesis (IL-4, IL-10 and PGE2) in murine bone-marrow-derived macrophages. Biochem Biophys Res Commun. 1995. Vol. 206(2):667-73

[74]

Gallardo-Soler A, Gómez-Nieto C, Campo ML, Tontonoz P, Castrillo A, et al.. Marathe C, Arginase I induction by modified lipoproteins in macrophages: a peroxisome proliferator-activated receptor-gamma/delta-mediated effect that links lipid metabolism and immunity. Mol Endocrinol. 2008. Vol. 22(6):1394-402

[75]

Khallou-Laschet J, Varthaman A, Fornasa G, Compain C, Gaston AT, Clement M, et al..Macrophage plasticity in experimental atherosclerosis. PLoS One. 2010. Vol. 5(1):e8852

[76]

Chandra S, Romero MJ, Shatanawi A, Alkilany AM, Caldwell RB, Caldwell RW. Oxidative species increase arginase activity in endothelial cells through the RhoA/rho kinase pathway. Br J Pharmacol. 2012. Vol. 165(2):506-19

[77]

Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arte-rioscler Thromb Vasc Biol. 2004. Vol. 24(6):1023-30

[78]

Rodionov RN, Murry DJ, Vaulman SF, Stevens JW, Lentz SR. Human alanine-glyoxylate aminotransferase 2 lowers asymmetric dimethylarginine and protects from inhibition of nitric oxide production. J Biol Chem. 2010. Vol. 285(8):5385-91

[79]

Schlesinger S, Sonntag SR, Lieb W, Maas R. Asymmetric and symmetric dimethylarginine as risk markers for total mortality and cardiovascular outcomes: a systematic review and meta-analysis of prospective studies. PLoS One. 2016. Vol. 11(11):e0165811

[80]

Zhou S, Zhu Q, Li X, Chen C, Liu J, Ye Y, et al.. Asymmetric dimethylarginine and all-cause mortality: a systematic review and meta-analysis. Sci Rep. 2017. Vol. 7:44692

[81]

Dowsett L, Duluc L, Higgins E, Alghamdi F, Fast W, Salt IP, et al.. Asymmetric dimethylarginine positively modulates calcium-sensing receptor signalling to promote lipid accumulation. Cell Signal. 2023. Vol. 107:110676

[82]

Adams MR, Jessup W, Hailstones D, Celermajer DS. L-arginine reduces human monocyte adhesion to vascular endothelium and endothelial expression of cell adhesion molecules. Circulation. 1997. Vol. 95(3):662-8

[83]

Ceremuzyński L, Chamiec T, Herbaczyńska-Cedro K. Effect of supplemental oral L-arginine on exercise capacity in patients with stable angina pectoris. Am J Cardiol. 1997. Vol. 80(3):331-3

[84]

Lerman A, Burnett JC Jr, Higano ST, McKinley LJ, Holmes DR Jr. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans. Circulation. 1998. Vol. 97(21):2123-8

[85]

Menzel D, Haller H, Wilhelm M, Robenek H. L-arginine and B vitamins improve endothelial function in subjects with mild to moderate blood pressure elevation. Eur J Nutr. 2018. Vol. 57(2):557-68

[86]

Schneider JY, Rothmann S, Schröder F, Langen J, Lücke T, Mariotti F, et al.. Effects of chronic oral L-arginine administration on the L-arginine/NO pathway in patients with peripheral arterial occlusive disease or coronary artery disease: L-arginine prevents renal loss of nitrite, the major NO reservoir. Amino Acids. 2015. Vol. 47(9):1961-74

[87]

Riccioni G, Scotti L, Guagnano MT, Bosco G, Bucciarelli V, Di Ilio E, et al..Physical exercise reduces synthesis of ADMA, SDMA, and L-arg. Front Biosci (Elite Ed). 2015. Vol. 7(3):417-22

[88]

Serban C, Sahebkar A, Ursoniu S, Mikhailidis DP, Rizzo M, Lip GYH, et al.. A systematic review and meta-analysis of the effect of statins on plasma asymmetric dimethylarginine concentrations. Sci Rep. 2015. Vol. 5:9902

[89]

Carlström M, Persson AEG, Larsson E, Hezel M, Scheffer PG, Teerlink T, et al.. Dietary nitrate attenuates oxidative stress, prevents cardiac and renal injuries, and reduces blood pressure in salt-induced hypertension. Cardiovasc Res. 2011. Vol. 89(3):574-85

[90]

Blum A, Hathaway L, Mincemoyer R, Schenke WH, Kirby M, Csako G, et al.. Oral L-arginine in patients with coronary artery disease on medical management. Circulation. 2000. Vol. 101(18):2160-4

[91]

Oomen CM, van Erk MJ, Feskens EJ, Kok FJ, Kromhout D. Arginine intake and risk of coronary heart disease mortality in elderly men. Arterioscler Thromb Vasc Biol. 2000. Vol. 20(9):2134-9

[92]

Hirooka Y, Imaizumi T, Tagawa T, Shiramoto M, Endo T, Ando S, et al.. Effects of L-arginine on impaired acetylcholine-induced and ischemic vasodilation of the forearm in patients with heart failure. Circulation. 1994. Vol. 90(2):658-68

[93]

Schulman SP, Becker LC, Kass DA, Champion HC, Terrin ML, Forman S, et al.. L-arginine therapy in acute myocardial infarction: the Vascular Interaction with Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial. J Am Med Assoc. 2006. Vol. 295(1):58-64

[94]

Miyata N, Zou AP, Mattson DL, Cowley AW Jr. Renal medullary interstitial infusion of L-arginine prevents hypertension in Dahl salt-sensitive rats. Am J Physiol. 1998. Vol. 275(5):R1667-73

[95]

Ono H, Ono Y, Frohlich ED. L-arginine reverses severe nephrosclerosis in aged spontaneously hypertensive rats. J Hypertens. 1999. Vol. 17(1):121-8

[96]

Higashi Y, Oshima T, Watanabe M, Matsuura H, Kajiyama G. Renal response to L-arginine in salt-sensitive patients with essential hypertension. Hypertension. 1996. Vol. 27(3 Pt2):643-8

[97]

Campese VM, Amar M, Anjali C, Medhat T, Wurgaft A. Effect of L-arginine on systemic and renal haemodynamics in salt-sensitive patients with essential hypertension. J Hum Hypertens. 1997. Vol. 11(8):527-32

[98]

Teunis CJ, Stroes ESG, Boekholdt SM, Wareham NJ, Murphy AJ, Nieuwdorp M, et al.. Tryptophan metabolites and incident cardiovascular disease: the EPIC-Norfolk prospective population study. Atherosclerosis. 2023. Vol. 387:117344

[99]

Lopez-Vilchez I, Diaz-Ricart M, White JG, Escolar G, Galan AM. Serotonin enhances platelet procoagulant properties and their activation induced during platelet tissue factor uptake. Cardiovasc Res. 2009. Vol. 84(2):309-16

[100]

Liang H, Chen M, Qi F, Shi L, Duan Z, Yang R, et al.. The proatherosclerotic function of indoleamine 2,3-dioxygenase 1 in the developmental stage of atherosclerosis. Signal Transduct Target Ther. 2019. Vol. 4:23

[101]

Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, et al.. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005. Vol. 22(5):633-42

[102]

Ketelhuth DFJ. The immunometabolic role of indoleamine 2,3-dioxygenase in atherosclerotic cardiovascular disease: immune homeostatic mechanisms in the artery wall. Cardiovasc Res. 2019. Vol. 115(9):1408-15

[103]

Forteza MJ, Polyzos KA, Baumgartner R, Suur BE, Mussbacher M, Johansson DK, et al.. Activation of the regulatory T-cell/indoleamine 2,3-dioxygenase axis reduces vascular inflammation and atherosclerosis in hyperlipidemic mice. Front Immunol. 2018. Vol. 9:950

[104]

Cole JE, Astola N, Cribbs AP, Goddard ME, Park I, Green P, et al.. Indoleamine 2,3-dioxygenase-1 is protective in atherosclerosis and its metabolites provide new opportunities for drug development. Proc Natl Acad Sci U S A. 2015. Vol. 112(42):13033-8

[105]

Zhang L, Ovchinnikova O, Jönsson A, Lundberg AM, Berg M, Hansson GK, et al.. The tryptophan metabolite 3-hydroxyanthranilic acid lowers plasma lipids and decreases atherosclerosis in hypercholesterolaemic mice. Eur Heart J. 2012. Vol. 33(16):2025-34

[106]

Neumann J, Hofmann B, Dhein S, Gergs U. Cardiac roles of serotonin (5-HT) and 5-HT-receptors in health and disease. Int J Mol Sci. 2023. Vol. 24(5):4765

[107]

Harris DD, Li J, Sabe SA, Banerjee D, Pearson E, Nho JW, et al.. Patients with uncontrolled hypertension subjected to cardiopulmonary bypass have altered coronary vasomotor responses to serotonin. Surgery. 2024. Vol. 176(2):274-81

[108]

Flanagan TW, Sebastian MN, Battaglia DM, Foster TP, Maillet EL, Nichols CD. Activation of 5-HT2 receptors reduces inflammation in vascular tissue and cholesterol levels in high-fat diet-fed apolipoprotein e knockout mice. Sci Rep. 2019. Vol. 9(1):13444

[109]

Wang H, Gao XY, Rao F, Yang H, Wang ZY, Liu L, et al.. Mechanism of contractile dysfunction induced by serotonin in coronary artery in spontaneously hypertensive rats. Naunyn Schmiedebergs Arch Pharmacol. 2020. Vol. 393(11):2165-76

[110]

García JJ, López-Pingarrón L, Almeida-Souza P, Tres A, Escudero P, García-Gil FA, et al.. Protective effects of melatonin in reducing oxidative stress and in preserving the fluidity of biological membranes: a review. J Pineal Res. 2014. Vol. 56(3):225-37

[111]

Cheng HH, Kuo CC, Yan JL, Chen HL, Lin WC, Wang KH, et al.. Control of cyclooxygenase-2 expression and tumorigenesis by endogenous 5-methoxytryptophan. Proc Natl Acad Sci U S A. 2012. Vol. 109(33):13231-6

[112]

Wang YF, Hsu YJ, Wu HF, Lee GL, Yang YS, Wu JY, et al.. Endothelium-derived 5-methoxytryptophan is a circulating anti-inflammatory molecule that blocks systemic inflammation. Circ Res. 2016. Vol. 119(2):222-36

[113]

Chu LY, Wang YF, Cheng HH, Kuo CC, Wu KK. Endothelium-derived 5-methoxytryptophan protects endothelial barrier function by blocking p38 MAPK activation. PLoS One. 2016. Vol. 11(3):e0152166

[114]

Chou HC, Chan HL. 5-methoxytryptophan-dependent protection of cardiomyocytes from heart ischemia reperfusion injury. Arch Biochem Biophys. 2014. Vol. 543:15-22

[115]

Apte RS, Chen DS, Ferrara N. VEGF in signaling and disease: beyond discovery and development. Cell. 2019. Vol. 176(6):1248-64

[116]

Lin YH, Kuo CC, Lee CM, Chou CH, Chen YH, Yeh JF, et al.. 5-methoxytryptophan is a potential marker for post-myocardial infarction heart failure -a preliminary approach to clinical utility. Int J Cardiol. 2016. Vol. 222:895-900

[117]

Li Q, You Y, Zeng Y, Wang X, Pan Z, Pang J, et al.. Associations between plasma tryptophan and indole-3-propionic acid levels and mortality in patients with coronary artery disease. Am J Clin Nutr. 2022. Vol. 116(4):1070-7

[118]

Geddo F, Antoniotti S, Gallo MP, Querio G. Indole-3-propionic acid, a gut microbiota-derived tryptophan metabolite, promotes endothelial dysfunction impairing purinergic-induced nitric oxide release in endothelial cells. Int J Mol Sci. 2024. Vol. 25(6):3389

[119]

Xue H, Chen X, Yu C, Deng Y, Zhang Y, Chen S, et al.. Gut microbially produced indole-3-propionic acid inhibits atherosclerosis by promoting reverse cholesterol transport and its deficiency is causally related to atherosclerotic cardiovascular disease. Circ Res. 2022. Vol. 131(5):404-20

[120]

Wang Q, Lv H, Ainiwan M, Yesitayi G, Abudesimu A, Siti D, et al.. Untargeted metabolomics identifies indole-3-propionic acid to relieve Ang II-induced endothelial dysfunction in aortic dissection. Mol Cell Biochem. 2024. Vol. 479(7):1767-86

[121]

Ji Y, Yin W, Liang Y, Sun L, Yin Y, Zhang W. Anti-inflammatory and anti-oxidative activity of indole-3-acetic acid involves induction of HO-1 and neutralization of free radicals in RAW264.7 cells. Int J Mol Sci. 2020. Vol. 21(5):1579

[122]

Ma X, Yang J, Yang G, Li L, Hao X, Wang G, et al.. A tryptophan metabolite of the microbiota improves neovascularization in diabetic limb ischemia. Front Cardiovasc Med. 2022. Vol. 9:910323

[123]

Konopelski P, Konop M, Gawrys-Kopczynska M, Podsadni P, Szczepanska A, Ufnal M. Indole-3-propionic acid, a tryptophan-derived bacterial metabolite, reduces weight gain in rats. Nutrients. 2019. Vol. 11(3):591

[124]

Ayaso R, Ghattas H, Abiad M, Obeid O. Meal pattern of male rats maintained on amino acid supplemented diets: the effect of tryptophan, lysine, arginine, proline and threonine. Nutrients. 2014. Vol. 6(7):2509-22

[125]

Gartner SN, Aidney F, Klockars A, Prosser C, Carpenter EA, Isgrove K, et al.. Intragastric preloads of l-tryptophan reduce ingestive behavior via oxytocinergic neural mechanisms in male mice. Appetite. 2018. Vol. 125:278-86

[126]

Wolf WA, Kuhn DM. Effects of L-tryptophan on blood pressure in normotensive and hypertensive rats. J Pharmacol Exp Ther. 1984. Vol. 230(2):324-9

[127]

Feltkamp H, Meurer KA, Godehardt E. Tryptophan-induced lowering of blood pressure and changes of serotonin uptake by platelets in patients with essential hypertension. Klin Wochenschr. 1984. Vol. 62(23):1115-9

[128]

Behr C, Kamp H, Fabian E, Krennrich G, Mellert W, Peter E, et al.. Gut microbiome-related metabolic changes in plasma of antibiotic-treated rats. Arch Toxicol. 2017. Vol. 91(10):3439-54

[129]

Song P, Ramprasath T, Wang H, Zou MH. Abnormal kynurenine pathway of tryptophan catabolism in cardiovascular diseases. Cell Mol Life Sci. 2017. Vol. 74(16):2899-916

[130]

Peng YH, Ueng SH, Tseng CT, Hung MS, Song JS, Wu JS, et al.. Important hydrogen bond networks in indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor design revealed by crystal structures of imidazoleisoindole derivatives with IDO1. J Med Chem. 2016. Vol. 59(1):282-93

[131]

Ramprasath T, Han YM, Zhang D, Yu CJ, Zou MH. Tryptophan catabolism and inflammation: a novel therapeutic target for aortic diseases. Front Immunol. 2021. Vol. 12:731701

[132]

Lu J, Wang H, Zhang H, Li J, Li H, Chen Q, et al.. Gut metabolite indole-3-propionic acid regulates macrophage autophagy through PPT1 inhibiting aging-related myocardial fibrosis. Adv Sci (Weinh). 2025. Vol. 12(34):e01070

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