Intermittent fasting (IF) is an intervention that can be beneficial for health span and mitigate the risk of developing age-related cardiovascular diseases; however, the involved mechanisms are not well understood. The present study investigated the effects of IF regimens on the plasma level of angiotensin II (Ang II), and the expression of Ang II receptors (AT1aR and AT2R) and angiotensin-converting enzyme 2 (ACE2) in the heart and aorta of male, 3-, 12-, and 24-month-old Wistar rats fed ad libitum (AL), fed ad libitum and fasted 1 day per week (FW), or fasted every other day (EOD) for 3 months.
Aging was associated with high circulating levels of Ang II, high level of AT1aR protein expression in the heart and aorta, and low level of AT2R protein expression in the heart and aorta. Both FW and EOD decreased Ang II levels (p < 0.01, p < 0.001) and AT1aR protein expression in the heart (p < 0.01, p < 0.001) and aorta (p < 0.001) of old rats. Both FW and EOD increased the expression of AT2R protein in the heart (p < 0.05 and p < 0.001, respectively). However, only EOD increased the expression of AT2R protein (p < 0.05) in the aorta. In the old group, both the FW and EOD regimens induced a significant increase in the expression of ACE2 protein in the heart (p < 0.01, p < 0.001 vs. age-matched AL group, respectively).
The results suggest that a part of the recovery effect of fasting on cardiovascular system in old rats is mediated through restoration of the balance of renin–angiotensin system.
SinghH, KaurT, ManchandaS, KaurG. Intermittent fasting combined with supplementation with Ayurvedic herbs reduces anxiety in middle aged female rats by anti-inflammatory pathways. Biogerontology, 2017; 18:601–614.
3.
CameloL, Souza MarinhoTD, ÁguilaMB, Souza-MelloV, Barbosa-da-SilvaS. Intermittent fasting exerts beneficial metabolic effects on blood pressure and cardiac structure by modulating local renin-angiotensin system in the heart of mice fed high-fat or high-fructose diets. Nutr Res, 2019; 63:51–62.
4.
BadrehF, JoukarS, BadaviM, RashnoM, DeheshT.The effects of age and fasting models on blood pressure, insulin/glucose profile and expression of longevity proteins in male rats. Rejuvenation Res, 2019. [Epub ahead of print]; DOI: 10.1089/rej.2019.2205.
5.
HeilbronnLK, CivitareseAE, SmithSR, HulverM, RavussinE. Glucose tolerance and skeletal muscle gene expression in response to alternate day fasting. Obes Res, 2005; 13:574–581.
6.
VaradyKA, BhutaniS, KlempelMC, et al.Alternate day fasting for weight loss in normal weight and overweight subjects: A randomized controlled trial. Nutr J, 2013; 12:146.
7.
MalinowskiB, ZalewskaK, WesierskaA, et al.Intermittent fasting in cardiovascular disorders—An overview. Nutrients, 2019; 11:673.
8.
KerndtPR, NaughtonJL, DriscollCE, LoxterkampDA. Fasting: The history, pathophysiology and complications. West J Med, 1982; 137:379.
9.
AhmetI, WanR, MattsonMP, LakattaEG. Cardioprotection by intermittent fasting in rats. Circulation, 2005; 112:3115–3121.
10.
GodarRJ, MaX, LiuH, et al.Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury. Autophagy, 2015; 11:1537–1560.
11.
CastelloL, FroioT, MainaM, et al.Alternate-day fasting protects the rat heart against age-induced inflammation and fibrosis by inhibiting oxidative damage and NF-Kb activation. Free Radic Biol Med, 2010; 48:47–54.
12.
SuzukiY, Ruiz-OrtegaM, Gomez-GuerreroC, TominoY, EgidoJ. Angiotensin II, the immune system and renal diseases: Another road for RAS?. Nephrol Dial Transplant, 2003; 18:1423–1426.
13.
DampneyRA, TanPS, SheriffMJ, FontesMA, HoriuchiJ. Cardiovascular effects of angiotensin II in the rostral ventrolateral medulla: The push-pull hypothesis. Curr Hypertens Rep, 2007; 9:222–227.
14.
de CavanaghEM, PiotrkowskiB, FragaCG. Concerted action of the renin-angiotensin system, mitochondria, and antioxidant defenses in aging. Mol Aspects Med, 2004; 25:27–36.
15.
GriendlingKK, MinieriCA, OllerenshawJD, AlexanderRW. Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells. Circ Res, 1994; 74:1141–1148.
16.
WangM, TakagiG, AsaiK, et al.Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates. Hypertension, 2003; 41:1308–1316.
17.
LinL, LiuX, XuJ, et al.Mas receptor mediates cardioprotection of angiotensin-(1–7) against Angiotensin II-induced cardiomyocyte autophagy and cardiac remodelling through inhibition of oxidative stress. J Cell Mol Med, 2016; 20:48–57.
18.
YadavA, VallabuS, AroraS, et al.ANG II promotes autophagy in podocytes. Am J Physiol Cell Physiol, 2010; 299:488–496.
19.
CaoXJ, LiYF. Alteration of messenger RNA and protein levels of cardiac alpha-adrenergic receptor and angiotensin II receptor subtypes during aging in rats. Can J Cardiol, 2009; 25:415–420.
20.
Raji-AmirhasaniA, JoukarS, Naderi-BoldajiV, BejeshkMA. Mild exercise along with limb blood-flow restriction modulates the electrocardiogram, angiotensin, and apelin receptors of the heart in aging rats. Iran J Basic Med Sci, 2018; 21:558–563.
21.
BejeshkMA, JoukarS, ShahouzehiB, et al.Combinatorial effect of lower extremity blood flow restriction and low intensity endurance exercise on aorta of old male rats: Histomorphological and molecular approach. Artery Res, 2018; 24:22e31.
22.
KamoT, AkazawaH, KomuroI. Pleiotropic effects of angiotensin II receptor signaling in cardiovascular homeostasis and aging. Int Heart J, 2015; 56:249–254.
23.
JonesES, BlackMJ, WiddopRE. Angiotensin AT2 receptor contributes to cardiovascular remodeling of aged rats during chronicAT1 receptor blockade. J Mol Cell Cardiol, 2004; 37:1023–1030.
24.
TakatsuM, NakashimaC, TakahashiK, et al.Calorie restriction attenuates cardiac remodeling and diastolic dysfunction in a rat model of metabolic syndrome. Hypertension, 2013; 62:957–65.
25.
BayatGR, HajizadehS, JavanM, et al.Effect of exercise and chronic administration of nandrolone decanoate on expression of rat heart sarcolemmal ATP-sensitive potassium channels. Feyz, 2012; 16:102–111.
26.
RenziCP, TanakaH, SugawaraJ. Effects of leg blood flow restriction during walking on cardiovascular function. Med Sci Sports Exerc, 2010; 42:726–732.
27.
CastelloL, MainaM, TestaG, et al.Alternate day fasting reverses the age associated hypertrophy phenotype in rat heart by influencing the ERK and PI3K signaling pathways. Mech Ageing Dev, 2011; 132:305–314.
28.
HiguchiS, OhtsuH, SuzukiH, ShiraiH, FrankGD, EguchiS. Angiotensin II signal transduction through the AT1 receptor: Novel insights into mechanisms and pathophysiology. Clin Sci (Lond), 2007; 112:417–428.
29.
MehtaPK, GriendlingKK. Angiotensin II cell signaling: Physiological and pathological effects in the cardiovascular system. Am J Physiol Cell Physiol, 2007; 292:C82–C97.
30.
KimS, IwaoH. Activation of mitogen-activated protein kinases in cardiovascular hypertrophy and remodeling. Jpn J Pharmacol, 1999; 80:97–102.
31.
KimS, IwaoH. Stress and vascular responses: Mitogen-activated protein kinases and activator protein-1 as promising therapeutic targets of vascular remodeling. J Pharmacol Sci, 2003; 91:177–181.
32.
WangY, SuB, SahVP, BrownJH, HanJ, ChienKR. Cardiac hypertrophy induced by mitogen-activated protein kinase 7, a specific activator for c-Jun NH2-terminal kinase in ventricular muscle cells. J Biol Chem, 1998; 273:5423–5426.
33.
ForresterSJ, BoozGW, SigmundCD, et al.Angiotensin II signal transduction: An update on mechanisms of physiology and pathophysiology. Physiol Rev, 2018; 98:1627–1738.
34.
DaiDF, SantanaLF, VermulstM, et al.Overexpression of catalase targeted to mitochondria attenuates murine cardiac aging. Circulation, 2009; 119:2789–2797.
35.
GrobanL, PailesNA, BennettCD, et al.Growth hormone replacement attenuates diastolic dysfunction and cardiac angiotensin II expression in senescent rats. J Gerontol A Biol Sci Med Sci, 2006; 61:28–35.
36.
SumnersC, de KloetAD, KrauseEG, UngerT, SteckelingsUM. Angiotensin type 2 receptors: Blood pressure regulation and end organ damage. Curr Opin Pharmacol, 2015; 21:115–121.
37.
PadiaSH, CareyRM. AT2 receptors: Beneficial counter-regulatory role in cardiovascular and renal function. Pflugers Arch, 2013; 465:99–110.
LiY, LiX-H, YuanH. Angiotensin II type-2 receptor-specific effects on the cardiovascular system. Cardiovasc Diagn Ther, 2012; 2:56–62.
40.
KondoM, ShibataR, MiuraR, et al.Caloric restriction stimulates revascularization in response to ischemia via adiponectin-mediated activation of endothelial nitric-oxide synthase. J Biol Chem, 2009; 284:1718–1724.
41.
Simões E SilvaAC, TeixeiraMM. ACE inhibition, ACE2 and angiotensin-(1–7) axis in kidney and cardiac inflammation and fibrosis. Pharmacol Res, 2016; 107:154–162.
42.
de CavanaghEM, InserraF, FerderL. Angiotensin II blockade: How its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition. Am J Physiol Heart Circ Physiol, 2015; 309:H15–H44.
