Investigating the Role of Cannabinoid Type 1 Receptors in Vascular Function and Remodeling in a Hypercholesterolemic Mouse Model with Low-Density Lipoprotein–Cannabinoid Type 1 Receptor Double Knockout Animals
Abstract
:1. Introduction
2. Results
2.1. Body Weight and Heart Weight Values
2.2. Cholesterol Level Measurements
2.3. Blood Pressure Measurements
2.4. Endothelium-Dependent Vasodilation of Abdominal Aortic Segments
2.5. Effects of Specific Inhibitors on Acetylcholine-Induced Vasodilatory Responses
2.6. Comparison of the Effects of NOS Inhibitor LNA on Acetylcholine-Induced Vasodilatory Responses
2.7. Immunohistochemistry Results for Endothelial NOS
3. Discussion
3.1. Vascular Alterations in Hypercholesterolemic LDLR-KO Mice
3.2. Vascular Effects of CB1 Receptors and Endocannabinoid Signaling, CB1R-KO Mice
3.3. Role of CB1 Receptors in Hypercholesterolemia-Induced Vascular Alterations in CB1R–LDLR Double-KO Mice
3.4. Roles of the Endocannabinoid System and CB1 Receptors in Cardiovascular Pathologies, Vascular Remodeling, and Possible Therapeutic Effects
4. Materials and Methods
4.1. Chemicals
4.2. Animals
4.3. Cholesterol Level Determination
4.4. Blood Pressure Measurement
4.5. Myography
4.6. Immunohistochemistry
4.7. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Akhmedov, A.; Sawamura, T.; Chen, C.H.; Kraler, S.; Vdovenko, D.; Lüscher, T.F. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1): A crucial driver of atherosclerotic cardiovascular disease. Eur. Heart J. 2021, 42, 1797–1807. [Google Scholar] [CrossRef]
- Dörnyei, G.; Vass, Z.; Juhász, C.B.; Nádasy, G.L.; Hunyady, L.; Szekeres, M. Role of the Endocannabinoid System in Metabolic Control Processes and in the Pathogenesis of Metabolic Syndrome: An Update. Biomedicines 2023, 11, 306. [Google Scholar] [CrossRef] [PubMed]
- Jiang, H.; Zhou, Y.; Nabavi, S.M.; Sahebkar, A.; Little, P.J.; Xu, S.; Weng, J.; Ge, J. Mechanisms of Oxidized LDL-Mediated Endothelial Dysfunction and Its Consequences for the Development of Atherosclerosis. Front. Cardiovasc. Med. 2022, 9, 925923. [Google Scholar] [CrossRef] [PubMed]
- Nedkoff, L.; Briffa, T.; Zemedikun, D.; Herrington, S.; Wright, F.L. Global Trends in Atherosclerotic Cardiovascular Disease. Clin. Ther. 2023, 45, 1087–1091. [Google Scholar] [CrossRef] [PubMed]
- Singh, R.B.; Mengi, S.A.; Xu, Y.J.; Arneja, A.S.; Dhalla, N.S. Pathogenesis of atherosclerosis: A multifactorial process. Exp. Clin. Cardiol. 2002, 7, 40–53. [Google Scholar]
- Zhou, R.; Stouffer, G.A.; Frishman, W.H. Cholesterol Paradigm and Beyond in Atherosclerotic Cardiovascular Disease: Cholesterol, Sterol Regulatory Element-Binding Protein, Inflammation, and Vascular Cell Mobilization in Vasculopathy. Cardiol. Rev. 2022, 30, 267–273. [Google Scholar] [CrossRef]
- Centa, M.; Ketelhuth, D.F.J.; Malin, S.; Gisterå, A. Quantification of Atherosclerosis in Mice. J. Vis. Exp. 2019, 148, e59828. [Google Scholar] [CrossRef]
- Devesa, A.; Ibanez, B.; Malick, W.A.; Tinuoye, E.O.; Bustamante, J.; Peyra, C.; Rosenson, R.S.; Bhatt, D.L.; Stone, G.W.; Fuster, V. Primary Prevention of Subclinical Atherosclerosis in Young Adults: JACC Review Topic of the Week. J. Am. Coll. Cardiol. 2023, 82, 2152–2162. [Google Scholar] [CrossRef]
- Mineo, C. Lipoprotein receptor signalling in atherosclerosis. Cardiovasc. Res. 2020, 116, 1254–1274. [Google Scholar] [CrossRef]
- Baltieri, N.; Guizoni, D.M.; Victorio, J.A.; Davel, A.P. Protective Role of Perivascular Adipose Tissue in Endothelial Dysfunction and Insulin-Induced Vasodilatation of Hypercholesterolemic LDL Receptor-Deficient Mice. Front. Physiol. 2018, 9, 229. [Google Scholar] [CrossRef]
- Emini Veseli, B.; Perrotta, P.; De Meyer, G.R.A.; Roth, L.; Van der Donckt, C.; Martinet, W.; De Meyer, G.R.Y. Animal models of atherosclerosis. Eur. J. Pharmacol. 2017, 816, 3–13. [Google Scholar] [CrossRef] [PubMed]
- Maganto-Garcia, E.; Tarrio, M.; Lichtman, A.H. Mouse models of atherosclerosis. Curr. Protoc. Immunol. 2012, 96, 15.24.11–15.24.23. [Google Scholar] [CrossRef] [PubMed]
- Liu, Y.; Zhang, Y.; Zhu, H.; Shen, W.; Chen, Z.; Bai, J.; Shuang, T.; Chen, Q. Aucubin administration suppresses STING signaling and mitigated high-fat diet-induced atherosclerosis and steatohepatosis in LDL receptor deficient mice. Food Chem. Toxicol. 2022, 169, 113422. [Google Scholar] [CrossRef] [PubMed]
- Vuorio, A.; Watts, G.F.; Schneider, W.J.; Tsimikas, S.; Kovanen, P.T. Familial hypercholesterolemia and elevated lipoprotein(a): Double heritable risk and new therapeutic opportunities. J. Intern. Med. 2020, 287, 2–18. [Google Scholar] [CrossRef] [PubMed]
- Bjørnholm, K.D.; Skovsted, G.F.; Mitgaard-Thomsen, A.; Rakipovski, G.; Tveden-Nyborg, P.; Lykkesfeldt, J.; Povlsen, G.K. Liraglutide treatment improves endothelial function in the Ldlr-/- mouse model of atherosclerosis and affects genes involved in vascular remodelling and inflammation. Basic Clin. Pharmacol. Toxicol. 2021, 128, 103–114. [Google Scholar] [CrossRef]
- Bondarenko, A.I. Cannabinoids and Cardiovascular System. Adv. Exp. Med. Biol. 2019, 1162, 63–87. [Google Scholar] [CrossRef]
- Kunos, G.; Osei-Hyiaman, D.; Bátkai, S.; Sharkey, K.A.; Makriyannis, A. Should peripheral CB1 cannabinoid receptors be selectively targeted for therapeutic gain? Trends Pharmacol. Sci. 2009, 30, 1–7. [Google Scholar] [CrossRef]
- Di Marzo, V. The endocannabinoid system in obesity and type 2 diabetes. Diabetologia 2008, 51, 1356–1367. [Google Scholar] [CrossRef]
- Pacher, P.; Bátkai, S.; Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 2006, 58, 389–462. [Google Scholar] [CrossRef]
- Pacher, P.; Kogan, N.M.; Mechoulam, R. Beyond THC and Endocannabinoids. Annu. Rev. Pharmacol. Toxicol. 2020, 60, 637–659. [Google Scholar] [CrossRef]
- Pacher, P.; Kunos, G. Modulating the endocannabinoid system in human health and disease--successes and failures. FEBS J. 2013, 280, 1918–1943. [Google Scholar] [CrossRef]
- Pacher, P.; Mukhopadhyay, P.; Mohanraj, R.; Godlewski, G.; Bátkai, S.; Kunos, G. Modulation of the endocannabinoid system in cardiovascular disease: Therapeutic potential and limitations. Hypertension 2008, 52, 601–607. [Google Scholar] [CrossRef]
- Schurman, L.D.; Lu, D.; Kendall, D.A.; Howlett, A.C.; Lichtman, A.H. Molecular Mechanism and Cannabinoid Pharmacology. Handb. Exp. Pharmacol. 2020, 258, 323–353. [Google Scholar] [CrossRef] [PubMed]
- Szekeres, M.; Nádasy, G.L.; Turu, G.; Soltész-Katona, E.; Benyó, Z.; Offermanns, S.; Ruisanchez, É.; Szabó, E.; Takáts, Z.; Bátkai, S.; et al. Endocannabinoid-mediated modulation of Gq/11 protein-coupled receptor signaling-induced vasoconstriction and hypertension. Mol. Cell. Endocrinol. 2015, 403, 46–56. [Google Scholar] [CrossRef]
- Ueda, N.; Tsuboi, K.; Uyama, T.; Ohnishi, T. Biosynthesis and degradation of the endocannabinoid 2-arachidonoylglycerol. Biofactors 2011, 37, 1–7. [Google Scholar] [CrossRef] [PubMed]
- Pacher, P.; Steffens, S. The emerging role of the endocannabinoid system in cardiovascular disease. Semin. Immunopathol. 2009, 31, 63–77. [Google Scholar] [CrossRef] [PubMed]
- Pertwee, R.G. Endocannabinoids and Their Pharmacological Actions. Handb. Exp. Pharmacol. 2015, 231, 1–37. [Google Scholar] [CrossRef] [PubMed]
- Miklós, Z.; Wafa, D.; Nádasy, G.L.; Tóth, Z.E.; Besztercei, B.; Dörnyei, G.; Laska, Z.; Benyó, Z.; Ivanics, T.; Hunyady, L.; et al. Angiotensin II-Induced Cardiac Effects Are Modulated by Endocannabinoid-Mediated CB1 Receptor Activation. Cells 2021, 10, 724. [Google Scholar] [CrossRef]
- Szekeres, M.; Nádasy, G.L.; Soltész-Katona, E.; Hunyady, L. Control of myogenic tone and agonist induced contraction of intramural coronary resistance arterioles by cannabinoid type 1 receptors and endocannabinoids. Prostaglandins Other Lipid Mediat. 2018, 134, 77–83. [Google Scholar] [CrossRef]
- Gyombolai, P.; Pap, D.; Turu, G.; Catt, K.J.; Bagdy, G.; Hunyady, L. Regulation of endocannabinoid release by G proteins: A paracrine mechanism of G protein-coupled receptor action. Mol. Cell. Endocrinol. 2012, 353, 29–36. [Google Scholar] [CrossRef]
- Huang, S.; Xiao, P.; Sun, J. Structural basis of signaling of cannabinoids receptors: Paving a way for rational drug design in controling mutiple neurological and immune diseases. Signal Transduct. Target. Ther. 2020, 5, 127. [Google Scholar] [CrossRef] [PubMed]
- Pacher, P.; Bátkai, S.; Kunos, G. Cardiovascular pharmacology of cannabinoids. In Handbook of Experimental Pharmacology; Springer: Berlin/Heidelberg, Germany, 2005; pp. 599–625. [Google Scholar] [CrossRef]
- Di Marzo, V. New approaches and challenges to targeting the endocannabinoid system. Nat. Rev. Drug Discov. 2018, 17, 623–639. [Google Scholar] [CrossRef] [PubMed]
- Karpińska, O.; Baranowska-Kuczko, M.; Kloza, M.; Kozłowska, H. Endocannabinoids modulate Gq/11 protein-coupled receptor agonist-induced vasoconstriction via a negative feedback mechanism. J. Pharm. Pharmacol. 2018, 70, 214–222. [Google Scholar] [CrossRef] [PubMed]
- Szekeres, M.; Nádasy, G.L.; Turu, G.; Soltész-Katona, E.; Tóth, Z.E.; Balla, A.; Catt, K.J.; Hunyady, L. Angiotensin II induces vascular endocannabinoid release, which attenuates its vasoconstrictor effect via CB1 cannabinoid receptors. J. Biol. Chem. 2012, 287, 31540–31550. [Google Scholar] [CrossRef]
- Bányai, B.; Vass, Z.; Kiss, S.; Balogh, A.; Brandhuber, D.; Karvaly, G.; Kovács, K.; Nádasy, G.L.; Hunyady, L.; Dörnyei, G.; et al. Role of CB1 Cannabinoid Receptors in Vascular Responses and Vascular Remodeling of the Aorta in Female Mice. Int. J. Mol. Sci. 2023, 24, 16429. [Google Scholar] [CrossRef] [PubMed]
- Guillamat-Prats, R.; Rami, M.; Herzig, S.; Steffens, S. Endocannabinoid Signalling in Atherosclerosis and Related Metabolic Complications. Thromb. Haemost. 2019, 119, 567–575. [Google Scholar] [CrossRef]
- Getz, G.S.; Reardon, C.A. Do the Apoe-/- and Ldlr-/- Mice Yield the Same Insight on Atherogenesis? Arterioscler. Thromb. Vasc. Biol. 2016, 36, 1734–1741. [Google Scholar] [CrossRef]
- Bennett, M.R.; Sinha, S.; Owens, G.K. Vascular Smooth Muscle Cells in Atherosclerosis. Circ. Res. 2016, 118, 692–702. [Google Scholar] [CrossRef]
- Grootaert, M.O.J.; Moulis, M.; Roth, L.; Martinet, W.; Vindis, C.; Bennett, M.R.; De Meyer, G.R.Y. Vascular smooth muscle cell death, autophagy and senescence in atherosclerosis. Cardiovasc. Res. 2018, 114, 622–634. [Google Scholar] [CrossRef]
- Mahdinia, E.; Shokri, N.; Taheri, A.T.; Asgharzadeh, S.; Elahimanesh, M.; Najafi, M. Cellular crosstalk in atherosclerotic plaque microenvironment. Cell Commun. Signal 2023, 21, 125. [Google Scholar] [CrossRef]
- Novikova, O.A.; Laktionov, P.P.; Karpenko, A.A. Mechanisms Underlying Atheroma Induction: The Roles of Mechanotransduction, Vascular Wall Cells, and Blood Cells. Ann. Vasc. Surg. 2018, 53, 224–233. [Google Scholar] [CrossRef]
- Beamish, J.A.; He, P.; Kottke-Marchant, K.; Marchant, R.E. Molecular regulation of contractile smooth muscle cell phenotype: Implications for vascular tissue engineering. Tissue Eng. Part B Rev. 2010, 16, 467–491. [Google Scholar] [CrossRef]
- Bernardi, S.; Marcuzzi, A.; Piscianz, E.; Tommasini, A.; Fabris, B. The Complex Interplay between Lipids, Immune System and Interleukins in Cardio-Metabolic Diseases. Int. J. Mol. Sci. 2018, 19, 4058. [Google Scholar] [CrossRef]
- Godo, S.; Shimokawa, H. Endothelial Functions. Arterioscler. Thromb. Vasc. Biol. 2017, 37, e108–e114. [Google Scholar] [CrossRef]
- Mudau, M.; Genis, A.; Lochner, A.; Strijdom, H. Endothelial dysfunction: The early predictor of atherosclerosis. Cardiovasc. J. Afr. 2012, 23, 222–231. [Google Scholar] [CrossRef] [PubMed]
- Wang, Y.; Wang, T.; Luo, Y.; Jiao, L. Identification Markers of Carotid Vulnerable Plaques: An Update. Biomolecules 2022, 12, 1192. [Google Scholar] [CrossRef] [PubMed]
- Eckenstaler, R.; Ripperger, A.; Hauke, M.; Petermann, M.; Hemkemeyer, S.A.; Schwedhelm, E.; Ergün, S.; Frye, M.; Werz, O.; Koeberle, A.; et al. A Thromboxane A2 Receptor-Driven COX-2-Dependent Feedback Loop That Affects Endothelial Homeostasis and Angiogenesis. Arterioscler. Thromb. Vasc. Biol. 2022, 42, 444–461. [Google Scholar] [CrossRef] [PubMed]
- Koller, A.; Dörnyei, G.; Kaley, G. Flow-induced responses in skeletal muscle venules: Modulation by nitric oxide and prostaglandins. Am. J. Physiol. 1998, 275, H831–H836. [Google Scholar] [CrossRef]
- Szekeres, M.; Nádasy, G.L.; Kaley, G.; Koller, A. Nitric oxide and prostaglandins modulate pressure-induced myogenic responses of intramural coronary arterioles. J. Cardiovasc. Pharmacol. 2004, 43, 242–249. [Google Scholar] [CrossRef]
- Zhou, Y.; Khan, H.; Xiao, J.; Cheang, W.S. Effects of Arachidonic Acid Metabolites on Cardiovascular Health and Disease. Int. J. Mol. Sci. 2021, 22, 12029. [Google Scholar] [CrossRef]
- Bátkai, S.; Pacher, P.; Osei-Hyiaman, D.; Radaeva, S.; Liu, J.; Harvey-White, J.; Offertáler, L.; Mackie, K.; Rudd, M.A.; Bukoski, R.D.; et al. Endocannabinoids acting at cannabinoid-1 receptors regulate cardiovascular function in hypertension. Circulation 2004, 110, 1996–2002. [Google Scholar] [CrossRef] [PubMed]
- Dannert, M.T.; Alsasua, A.; Herradon, E.; Martín, M.I.; López-Miranda, V. Vasorelaxant effect of Win 55,212-2 in rat aorta: New mechanisms involved. Vascul Pharmacol. 2007, 46, 16–23. [Google Scholar] [CrossRef] [PubMed]
- Hillard, C.J. Endocannabinoids and vascular function. J. Pharmacol. Exp. Ther. 2000, 294, 27–32. [Google Scholar] [PubMed]
- Járai, Z.; Wagner, J.A.; Goparaju, S.K.; Wang, L.; Razdan, R.K.; Sugiura, T.; Zimmer, A.M.; Bonner, T.I.; Zimmer, A.; Kunos, G. Cardiovascular effects of 2-arachidonoyl glycerol in anesthetized mice. Hypertension 2000, 35, 679–684. [Google Scholar] [CrossRef]
- O’Sullivan, S.E.; Randall, M.D.; Gardiner, S.M. The in vitro and in vivo cardiovascular effects of Delta9-tetrahydrocannabinol in rats made hypertensive by chronic inhibition of nitric-oxide synthase. J. Pharmacol. Exp. Ther. 2007, 321, 663–672. [Google Scholar] [CrossRef]
- Randall, M.D.; Kendall, D.A.; O’Sullivan, S. The complexities of the cardiovascular actions of cannabinoids. Br. J. Pharmacol. 2004, 142, 20–26. [Google Scholar] [CrossRef]
- Wagner, J.A.; Járai, Z.; Bátkai, S.; Kunos, G. Hemodynamic effects of cannabinoids: Coronary and cerebral vasodilation mediated by cannabinoid CB1 receptors. Eur. J. Pharmacol. 2001, 423, 203–210. [Google Scholar] [CrossRef]
- Turu, G.; Hunyady, L. Signal transduction of the CB1 cannabinoid receptor. J. Mol. Endocrinol. 2010, 44, 75–85. [Google Scholar] [CrossRef]
- Cinar, R.; Iyer, M.R.; Kunos, G. The therapeutic potential of second and third generation CB1R antagonists. Pharmacol. Ther. 2020, 208, 107477. [Google Scholar] [CrossRef]
- Jamshidi, N.; Taylor, D.A. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br. J. Pharmacol. 2001, 134, 1151–1154. [Google Scholar] [CrossRef]
- Mastinu, A.; Premoli, M.; Ferrari-Toninelli, G.; Tambaro, S.; Maccarinelli, G.; Memo, M.; Bonini, S.A. Cannabinoids in health and disease: Pharmacological potential in metabolic syndrome and neuroinflammation. Horm. Mol. Biol. Clin. Investig. 2018, 36. [Google Scholar] [CrossRef] [PubMed]
- Langbein, H.; Hofmann, A.; Brunssen, C.; Goettsch, W.; Morawietz, H. Impact of high-fat diet and voluntary running on body weight and endothelial function in LDL receptor knockout mice. Atheroscler. Suppl. 2015, 18, 59–66. [Google Scholar] [CrossRef]
- Malinowska, B.; Baranowska-Kuczko, M.; Schlicker, E. Triphasic blood pressure responses to cannabinoids: Do we understand the mechanism? Br. J. Pharmacol. 2012, 165, 2073–2088. [Google Scholar] [CrossRef] [PubMed]
- Mukhopadhyay, P.; Mohanraj, R.; Bátkai, S.; Pacher, P. CB1 cannabinoid receptor inhibition: Promising approach for heart failure? Congest. Heart Fail. 2008, 14, 330–334. [Google Scholar] [CrossRef]
- Ho, W.S.; Gardiner, S.M. Acute hypertension reveals depressor and vasodilator effects of cannabinoids in conscious rats. Br. J. Pharmacol. 2009, 156, 94–104. [Google Scholar] [CrossRef] [PubMed]
- Sierra, S.; Luquin, N.; Navarro-Otano, J. The endocannabinoid system in cardiovascular function: Novel insights and clinical implications. Clin. Auton. Res. 2018, 28, 35–52. [Google Scholar] [CrossRef] [PubMed]
- Pertwee, R.G. Targeting the endocannabinoid system with cannabinoid receptor agonists: Pharmacological strategies and therapeutic possibilities. Philos. Trans. R. Soc. Lond. B Biol. Sci. 2012, 367, 3353–3363. [Google Scholar] [CrossRef]
- Fulmer, M.L.; Thewke, D.P. The Endocannabinoid System and Heart Disease: The Role of Cannabinoid Receptor Type 2. Cardiovasc. Hematol. Disord. Drug Targets 2018, 18, 34–51. [Google Scholar] [CrossRef]
- Kipnes, M.S.; Hollander, P.; Fujioka, K.; Gantz, I.; Seck, T.; Erondu, N.; Shentu, Y.; Lu, K.; Suryawanshi, S.; Chou, M.; et al. A one-year study to assess the safety and efficacy of the CB1R inverse agonist taranabant in overweight and obese patients with type 2 diabetes. Diabetes Obes. Metab. 2010, 12, 517–531. [Google Scholar] [CrossRef]
- Dol-Gleizes, F.; Paumelle, R.; Visentin, V.; Marés, A.M.; Desitter, P.; Hennuyer, N.; Gilde, A.; Staels, B.; Schaeffer, P.; Bono, F. Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler. Thromb. Vasc. Biol. 2009, 29, 12–18. [Google Scholar] [CrossRef]
- Tiyerili, V.; Zimmer, S.; Jung, S.; Wassmann, K.; Naehle, C.P.; Lütjohann, D.; Zimmer, A.; Nickenig, G.; Wassmann, S. CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function. Basic Res. Cardiol. 2010, 105, 465–477. [Google Scholar] [CrossRef] [PubMed]
- Steffens, S.; Mach, F. Cannabinoid receptors in atherosclerosis. Curr. Opin. Lipidol. 2006, 17, 519–526. [Google Scholar] [CrossRef] [PubMed]
- Steffens, S.; Veillard, N.R.; Arnaud, C.; Pelli, G.; Burger, F.; Staub, C.; Karsak, M.; Zimmer, A.; Frossard, J.L.; Mach, F. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature 2005, 434, 782–786. [Google Scholar] [CrossRef]
- Wei, T.T.; Chandy, M.; Nishiga, M.; Zhang, A.; Kumar, K.K.; Thomas, D.; Manhas, A.; Rhee, S.; Justesen, J.M.; Chen, I.Y.; et al. Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation. Cell 2022, 185, 1676–1693.e23. [Google Scholar] [CrossRef] [PubMed]
- Sharifi-Rad, J.; Quispe, C.; Imran, M.; Rauf, A.; Nadeem, M.; Gondal, T.A.; Ahmad, B.; Atif, M.; Mubarak, M.S.; Sytar, O.; et al. Genistein: An Integrative Overview of Its Mode of Action, Pharmacological Properties, and Health Benefits. Oxid. Med. Cell. Longev. 2021, 2021, 3268136. [Google Scholar] [CrossRef]
- Paszkiewicz, R.L.; Bergman, R.N.; Santos, R.S.; Frank, A.P.; Woolcott, O.O.; Iyer, M.S.; Stefanovski, D.; Clegg, D.J.; Kabir, M. A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided. Int. J. Mol. Sci. 2020, 21, 6639. [Google Scholar] [CrossRef]
- Zimmer, A.; Zimmer, A.M.; Hohmann, A.G.; Herkenham, M.; Bonner, T.I. Increased mortality, hypoactivity, and hypoalgesia in cannabinoid CB1 receptor knockout mice. Proc. Natl. Acad. Sci. USA 1999, 96, 5780–5785. [Google Scholar] [CrossRef]
- Hartvigsen, K.; Binder, C.J.; Hansen, L.F.; Rafia, A.; Juliano, J.; Hörkkö, S.; Steinberg, D.; Palinski, W.; Witztum, J.L.; Li, A.C. A diet-induced hypercholesterolemic murine model to study atherogenesis without obesity and metabolic syndrome. Arterioscler. Thromb. Vasc. Biol. 2007, 27, 878–885. [Google Scholar] [CrossRef]
- Baumer, Y.; McCurdy, S.; Jin, X.; Weatherby, T.M.; Dey, A.K.; Mehta, N.N.; Yap, J.K.; Kruth, H.S.; Boisvert, W.A. Ultramorphological analysis of plaque advancement and cholesterol crystal formation in Ldlr knockout mouse atherosclerosis. Atherosclerosis 2019, 287, 100–111. [Google Scholar] [CrossRef]
- Horváth, B.; Orsy, P.; Benyó, Z. Endothelial NOS-mediated relaxations of isolated thoracic aorta of the C57BL/6J mouse: A methodological study. J. Cardiovasc. Pharmacol. 2005, 45, 225–231. [Google Scholar] [CrossRef]
Group Number | Genotype | Diet | n |
---|---|---|---|
1. | CB1R+/+; LDLR+/+ | CD | 9 |
2. | CB1R−/−; LDLR+/+ | CD | 6 |
3. | CB1R+/+; LDLR−/− | CD | 7 |
4. | CB1R−/−; LDLR−/− | CD | 7 |
5. | CB1R+/+; LDLR+/+ | HFD | 10 |
6. | CB1R−/−; LDLR+/+ | HFD | 10 |
7. | CB1R+/+; LDLR−/− | HFD | 6 |
8. | CB1R−/−; LDLR−/− | HFD | 7 |
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Vass, Z.; Shenker-Horváth, K.; Bányai, B.; Vető, K.N.; Török, V.; Gém, J.B.; Nádasy, G.L.; Kovács, K.B.; Horváth, E.M.; Jakus, Z.; et al. Investigating the Role of Cannabinoid Type 1 Receptors in Vascular Function and Remodeling in a Hypercholesterolemic Mouse Model with Low-Density Lipoprotein–Cannabinoid Type 1 Receptor Double Knockout Animals. Int. J. Mol. Sci. 2024, 25, 9537. https://doi.org/10.3390/ijms25179537
Vass Z, Shenker-Horváth K, Bányai B, Vető KN, Török V, Gém JB, Nádasy GL, Kovács KB, Horváth EM, Jakus Z, et al. Investigating the Role of Cannabinoid Type 1 Receptors in Vascular Function and Remodeling in a Hypercholesterolemic Mouse Model with Low-Density Lipoprotein–Cannabinoid Type 1 Receptor Double Knockout Animals. International Journal of Molecular Sciences. 2024; 25(17):9537. https://doi.org/10.3390/ijms25179537
Chicago/Turabian StyleVass, Zsolt, Kinga Shenker-Horváth, Bálint Bányai, Kinga Nóra Vető, Viktória Török, Janka Borbála Gém, György L. Nádasy, Kinga Bernadett Kovács, Eszter Mária Horváth, Zoltán Jakus, and et al. 2024. "Investigating the Role of Cannabinoid Type 1 Receptors in Vascular Function and Remodeling in a Hypercholesterolemic Mouse Model with Low-Density Lipoprotein–Cannabinoid Type 1 Receptor Double Knockout Animals" International Journal of Molecular Sciences 25, no. 17: 9537. https://doi.org/10.3390/ijms25179537