Intracerebroventricularly Administered Apelin-13 Regulates Cardiovascular Parameters and SIRT1 Expression
Yıl 2026,
Cilt: 48 Sayı: 2, 343 - 351, 11.02.2026
Serdar Şahintürk
,
Naciye İşbil
,
Betül Çam
,
Ayşen Çakır
,
Cansu Badem
,
Mertcan Tekneci
,
Kasım Özlük
Öz
In this work, we examined the effects of apelin-13 intracerebroventricular injection on heart rate, blood pressure, cardiac contractility, and cardiac sirtuin 1 (SIRT1) level. Wistar rats received intracerebroventricular injections of either 10 µl saline or Apelin-13 (5, 10, and 20 nmol). First, heart rate and mean arterial blood pressure (MABP) were recorded. The second step was determining the left ventricular ±dP/dt values. After the rats' hearts were removed, the Western Blot method was used to measure the amount of SIRT1 in the heart tissues. 10 nmol of apelin-13 raised MABP. On the other hand, 20 nmol of apelin-13 reduced MABP. At 5 and 10 nmol, apelin-13 reduced heart rate. On the other hand, apelin-13 raised heart rate at a dose of 20 nmol. Apelin-13 raised +dP/dt values at 10 and 20 nmol dosages. -dP/dt readings were raised by apelin-13 at a dose of 20 nmol. SIRT1 levels in the cardiac tissues were raised by apelin-13 at a dose of 5 nmol. These results confirm that apelin is involved in the central control of heart rate, blood pressure, and cardiac contractility. The current investigation shows that apelin administered centrally improves left ventricular contractile function. Additionally, this study suggests that SIRT1 might be involved in the physiological effects of apelin on the cardiovascular system.
Etik Beyan
Ethical approval for this study was given by Bursa Uludağ University Animal Experiments Local Ethics Committee (number: 2015-07/06; date: 26.05.2015).
Destekleyen Kurum
Bursa Uludağ University Scientific Research Projects Unit
Proje Numarası
Proje numarası: OUAP(T)-2015/24.
Teşekkür
We would like to thank Bursa Uludağ University Scientific Research Projects Unit.
Kaynakça
-
1. Kuba K, Sato T, Imai Y, Yamaguchi T. Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology. Peptides. 2019;111:62-70.
-
2. Zhang Y, Wang Y, Lou Y, Luo M, Lu Y, Li Z, Wang Y, Miao L. Elabela, a newly discovered APJ ligand: Similarities and differences with Apelin. Peptides. 2018;109:23-32.
-
3. Mughal A, O'Rourke ST: Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacol Ther. 2018;190:139-47.
-
4. Yamaleyeva LM, Shaltout HA, Varagic J. Apelin-13 in blood pressure regulation and cardiovascular disease. Curr Opin Nephrol Hypertens. 2016;25(5):396-403.
-
5. Reaux A, De Mota N, Skultetyova I, et al. Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain. J Neurochem. 2001;77 (4):1085–96.
-
6. Farkasfalvi K, Stagg MA, Coppen SR, et al. Direct effects of apelin on cardiomyocyte contractility and electrophysiology. Biochem Biophys Res Commun. 2007;357(4):889-95.
-
7. Szokodi I, Tavi P, Földes G, et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res. 2002;91(5):434-40.
-
8. Folino A, Montarolo PG, Samaja M, Rastaldo R. Effects of apelin on the cardiovascular system. Heart Fail Rev. 2015;20(4):505-18.
-
9. Hou X, Zeng H, He X, Chen J-X. Sirt3 is essential for apelin-induced angiogenesis in post-myocardial infarction of diabetes. J Cell Mol Med. 2015;19(1):53-61.
-
10. Zhou Q, Chen L, Tang M, Guo Y, Li L: Apelin/APJ system: A novel promising target for anti-aging intervention. Clin Chim Acta. 2018;487:233-40.
-
11. Bindu S, Pillai VB, Gupta MP. Role of Sirtuins in Regulating Pathophysiology of the Heart. Trends Endocrinol Metab. 2016;27(8):563-73.
-
12. D'Onofrio N, Servillo L, Balestrieri ML. SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection. Antioxid Redox Signal. 2018;28(8):711-32.
-
13. Winnik S, Auwerx J, Sinclair DA, Matter CM. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J. 2015;36(48):3404-12.
-
14. Cakir A, Ocalan B, Koc C, Suyen GG, Cansev M, Nevzat Kahveci N. Effects of CDP-choline administration on learning and memory in REM sleep-deprived rats. Physiol Behav. 2020;213:112703.
-
15. Pliska V. Models to explain dose-response relationships that exhibit a downturn phase. Trends Pharmacol Sci. 1994;15(6):178-81.
-
16. Rovati GE, Nicosia S. Lower efficacy: İnteraction with an inhibitory receptor or partial agonism?. Trends Pharmacol Sci. 1994;15(5):140-4.
-
17. Kagiyama S, Fukuhara M, Matsumura K, Lin Y, Fujii K, Iida M. Central and peripheral cardiovascular actions of apelin in conscious rats. Regul Pept. 2005;125(1-3):55–9.
-
18. Cudnoch-Jedrzejewska A, Gomolka R, Szczepanska-Sadowska E, et al. High fat diet and chronic stress reduce central pressor and tachycardic effects of apelin in Sprague-Dawley rats. Clin Exp Pharmacol Physiol. 2015;42(1):52–62.
-
19. Seyedabadi M, Goodchild AK, Pilowsky PM. Site-specific effects of apelin-13 in the rat medulla oblongata on arterial pressure and respiration. Auton Neurosci-Basic. 2002;101(1-2):32-8.
-
20. Yao F, Modgil A, Zhang Q, et al. Pressor effect of apelin-13 in the rostral ventrolateral medulla: role of NAD(P)H oxidase-derived superoxide. J Pharmacol Exp Ther. 2011;336(2):372-80.
-
21. Zhang Q, Yao F, Raizada MK, O'Rourke ST, Sun C. Apelin gene transfer into the rostral ventrolateral medulla induces chronic blood pressure elevation in normotensive rats. Circ Res. 2009;104(12):1421-8.
-
22. Berry MF, Pirolli TJ, Jayasankar V, et al. Apelin has in vivo inotropic effects on normal and failing hearts. Circulation. 2004;110(11):187–93.
-
23. Barnes GD, Alam S, Carter G, et al. Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure. Circ Heart Fail. 2013;6:482–91.
-
24. Japp AG, Cruden NL, Barnes G, et al. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation. 2010;121(16):1818–27.
-
25. Hou X, Zeng H, Tuo QH, Liao D-F, Chen J-X. Apelin Gene Therapy Increases Autophagy via Activation of Sirtuin 3 in Diabetic Heart. Diabetes Res (Fairfax). 2015;1:84–91.
-
26. Fan J, Guang H, Zhang H, et al. SIRT1 Mediates Apelin-13 in Ameliorating Chronic Normobaric Hypoxia-induced Anxiety-like Behavior by Suppressing NF-κB Pathway in Mice Hippocampus, Neuroscience. 2018;381:22-34.
-
27. Yang R, Fang W, Liang J, et al. Apelin/APJ axis improves angiotensin II-induced endothelial cell senescence through AMPK/SIRT1 signaling pathway. Arch Med Sci. 2018;14(4):725-34.
-
28. Mattagajasingh I, Kim CS, Naqvi A, et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 2007;104(37):14855-60.
-
29. Mughal A, Sun C, O'Rourke ST. Activation of Large Conductance, Calcium-Activated Potassium Channels by Nitric Oxide Mediates Apelin-Induced Relaxation of Isolated Rat Coronary Arteries. J Pharmacol Exp Ther. 2018;366(2):265-73.
İntraserebroventriküler Uygulanan Apelin-13 Kardiyovasküler Parametreleri ve SIRT1 Ekspresyonunu Düzenler
Yıl 2026,
Cilt: 48 Sayı: 2, 343 - 351, 11.02.2026
Serdar Şahintürk
,
Naciye İşbil
,
Betül Çam
,
Ayşen Çakır
,
Cansu Badem
,
Mertcan Tekneci
,
Kasım Özlük
Öz
Bu çalışmada, intraserebroventriküler apelin-13 enjeksiyonunun kan basıncı, kalp hızı, kardiyak kontraktilite ve kardiyak sirtuin 1 (SIRT1) düzeyi üzerindeki etkilerini araştırdık. Apelin-13 (5, 10 ve 20 nmol) veya 10 µl salin, Wistar sıçanlarına intraserebroventriküler olarak enjekte edildi. İlk olarak, ortalama arteriyel kan basıncı (MABP) ve kalp hızı ölçüldü. İkinci olarak sol ventrikül ±dP/dt değerleri belirlendi. Son olarak sıçanların kalpleri çıkarıldı ve kalp dokularındaki SIRT1 seviyesi Western Blot yöntemi ile belirlendi. 10 nmol dozundaki apelin-13 MABP'yi artırdı. Bununla birlikte, 20 nmol dozundaki apelin-13 MABP'yi azalttı. 5 ve 10 nmol dozlarındaki apelin-13 kalp hızını azalttı. Bununla birlikte, 20 nmol dozundaki apelin-13 kalp hızını artırdı. 10 ve 20 nmol dozlarında apelin-13 +dP/dt değerlerini artırdı. 20 nmol dozunda apelin-13 –dP/dt değerlerini artırdı. 5 nmol dozundaki apelin-13, kalp dokularındaki SIRT1 düzeyini artırdı. Bu bulgular, apelinin kan basıncının, kalp hızının ve kardiyak kontraktilitenin merkezi düzenlemesine katıldığı gerçeğini desteklemektedir. Bu çalışma, apelinin santral uygulamasının sol ventrikül kontraktil performansını artırdığını göstermektedir. Ayrıca bu çalışma, SIRT1'in apelinin kardiyovasküler fizyolojik etkilerinde rol oynayabileceğine işaret etmektedir.
Etik Beyan
Bu çalışma için etik onay, Bursa Uludağ Üniversitesi Hayvan Deneyleri Yerel Etik Kurulu tarafından verilmiştir (numara: 2015-07/06; tarih: 26.05.2015).
Destekleyen Kurum
Bursa Uludağ Üniversitesi Bilimsel Araştırma Projeleri Birimi
Proje Numarası
Proje numarası: OUAP(T)-2015/24.
Teşekkür
Bursa Uludağ Üniversitesi Bilimsel Araştırma Projeleri Birimine teşekkür ederiz.
Kaynakça
-
1. Kuba K, Sato T, Imai Y, Yamaguchi T. Apelin and Elabela/Toddler; double ligands for APJ/Apelin receptor in heart development, physiology, and pathology. Peptides. 2019;111:62-70.
-
2. Zhang Y, Wang Y, Lou Y, Luo M, Lu Y, Li Z, Wang Y, Miao L. Elabela, a newly discovered APJ ligand: Similarities and differences with Apelin. Peptides. 2018;109:23-32.
-
3. Mughal A, O'Rourke ST: Vascular effects of apelin: Mechanisms and therapeutic potential. Pharmacol Ther. 2018;190:139-47.
-
4. Yamaleyeva LM, Shaltout HA, Varagic J. Apelin-13 in blood pressure regulation and cardiovascular disease. Curr Opin Nephrol Hypertens. 2016;25(5):396-403.
-
5. Reaux A, De Mota N, Skultetyova I, et al. Physiological role of a novel neuropeptide, apelin, and its receptor in the rat brain. J Neurochem. 2001;77 (4):1085–96.
-
6. Farkasfalvi K, Stagg MA, Coppen SR, et al. Direct effects of apelin on cardiomyocyte contractility and electrophysiology. Biochem Biophys Res Commun. 2007;357(4):889-95.
-
7. Szokodi I, Tavi P, Földes G, et al. Apelin, the novel endogenous ligand of the orphan receptor APJ, regulates cardiac contractility. Circ Res. 2002;91(5):434-40.
-
8. Folino A, Montarolo PG, Samaja M, Rastaldo R. Effects of apelin on the cardiovascular system. Heart Fail Rev. 2015;20(4):505-18.
-
9. Hou X, Zeng H, He X, Chen J-X. Sirt3 is essential for apelin-induced angiogenesis in post-myocardial infarction of diabetes. J Cell Mol Med. 2015;19(1):53-61.
-
10. Zhou Q, Chen L, Tang M, Guo Y, Li L: Apelin/APJ system: A novel promising target for anti-aging intervention. Clin Chim Acta. 2018;487:233-40.
-
11. Bindu S, Pillai VB, Gupta MP. Role of Sirtuins in Regulating Pathophysiology of the Heart. Trends Endocrinol Metab. 2016;27(8):563-73.
-
12. D'Onofrio N, Servillo L, Balestrieri ML. SIRT1 and SIRT6 Signaling Pathways in Cardiovascular Disease Protection. Antioxid Redox Signal. 2018;28(8):711-32.
-
13. Winnik S, Auwerx J, Sinclair DA, Matter CM. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J. 2015;36(48):3404-12.
-
14. Cakir A, Ocalan B, Koc C, Suyen GG, Cansev M, Nevzat Kahveci N. Effects of CDP-choline administration on learning and memory in REM sleep-deprived rats. Physiol Behav. 2020;213:112703.
-
15. Pliska V. Models to explain dose-response relationships that exhibit a downturn phase. Trends Pharmacol Sci. 1994;15(6):178-81.
-
16. Rovati GE, Nicosia S. Lower efficacy: İnteraction with an inhibitory receptor or partial agonism?. Trends Pharmacol Sci. 1994;15(5):140-4.
-
17. Kagiyama S, Fukuhara M, Matsumura K, Lin Y, Fujii K, Iida M. Central and peripheral cardiovascular actions of apelin in conscious rats. Regul Pept. 2005;125(1-3):55–9.
-
18. Cudnoch-Jedrzejewska A, Gomolka R, Szczepanska-Sadowska E, et al. High fat diet and chronic stress reduce central pressor and tachycardic effects of apelin in Sprague-Dawley rats. Clin Exp Pharmacol Physiol. 2015;42(1):52–62.
-
19. Seyedabadi M, Goodchild AK, Pilowsky PM. Site-specific effects of apelin-13 in the rat medulla oblongata on arterial pressure and respiration. Auton Neurosci-Basic. 2002;101(1-2):32-8.
-
20. Yao F, Modgil A, Zhang Q, et al. Pressor effect of apelin-13 in the rostral ventrolateral medulla: role of NAD(P)H oxidase-derived superoxide. J Pharmacol Exp Ther. 2011;336(2):372-80.
-
21. Zhang Q, Yao F, Raizada MK, O'Rourke ST, Sun C. Apelin gene transfer into the rostral ventrolateral medulla induces chronic blood pressure elevation in normotensive rats. Circ Res. 2009;104(12):1421-8.
-
22. Berry MF, Pirolli TJ, Jayasankar V, et al. Apelin has in vivo inotropic effects on normal and failing hearts. Circulation. 2004;110(11):187–93.
-
23. Barnes GD, Alam S, Carter G, et al. Sustained cardiovascular actions of APJ agonism during renin-angiotensin system activation and in patients with heart failure. Circ Heart Fail. 2013;6:482–91.
-
24. Japp AG, Cruden NL, Barnes G, et al. Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure. Circulation. 2010;121(16):1818–27.
-
25. Hou X, Zeng H, Tuo QH, Liao D-F, Chen J-X. Apelin Gene Therapy Increases Autophagy via Activation of Sirtuin 3 in Diabetic Heart. Diabetes Res (Fairfax). 2015;1:84–91.
-
26. Fan J, Guang H, Zhang H, et al. SIRT1 Mediates Apelin-13 in Ameliorating Chronic Normobaric Hypoxia-induced Anxiety-like Behavior by Suppressing NF-κB Pathway in Mice Hippocampus, Neuroscience. 2018;381:22-34.
-
27. Yang R, Fang W, Liang J, et al. Apelin/APJ axis improves angiotensin II-induced endothelial cell senescence through AMPK/SIRT1 signaling pathway. Arch Med Sci. 2018;14(4):725-34.
-
28. Mattagajasingh I, Kim CS, Naqvi A, et al. SIRT1 promotes endothelium-dependent vascular relaxation by activating endothelial nitric oxide synthase. Proc Natl Acad Sci U S A. 2007;104(37):14855-60.
-
29. Mughal A, Sun C, O'Rourke ST. Activation of Large Conductance, Calcium-Activated Potassium Channels by Nitric Oxide Mediates Apelin-Induced Relaxation of Isolated Rat Coronary Arteries. J Pharmacol Exp Ther. 2018;366(2):265-73.