Carvacrol Ameliorates Pathological Cardiac Hypertrophy in Both In-vivo and In-vitro Models

Document Type : Research article

Authors

1 Department of Physiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

2 Department of Microbiology, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

3 Department of Biochemistry, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

4 Yazd Reproductive Sciences Institute, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

5 Biotechnology Research Center, International Campus, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.

Abstract

Hypertension-induced left ventricular hypertrophy is the most important risk factor for heart failure. This study aimed at investigating the effects of monoterpenoid phenol, carvacrol, on myocardial hypertrophy using both in-vivo and in-vitro models. Male Wistar rats were divided into the control (Ctl), un-treated hypertrophy (H), and carvacrol-treated hypertrophy groups (25, 50 and 75 mg/kg/day, Car+H). In the hypertrophy groups animals underwent abdominal aorta banding. Blood pressure (BP) was recorded via carotid artery cannulation. TUNEL assay and Masson’s trichrome staining were used to assess apoptosis and fibrosis, respectively. The 2-2-diphenyl 1-picril-hydrasil)DPPH( radical scavenging activityand malondialdehyde (MDA) level were estimated by biochemical tests. In in-vitro study H9c2 cardiomyoblasts were treated with angiotensin II (Ang II) to promote hypertrophy. Cell size was measured using crystal violet staining. Gene expression was evaluated by real-timeRT-PCR technique. In the carvacrol-treated rats BP, heart rate, and heart weight to the body weight ratio were significantly decreased. In-vitro study showed that H9c2 cell size was significantly reduced compared to Ang II-treated cells. Both in-vivo and in-vitro studies demonstrated that carvacroldecreased atrial natriuretic peptide )ANP( mRNA level significantly (vs. H groups). The number of apoptotic cells increased in Hgroup, while it was decreased in the Car50+H and Car75+H. In Car+H groups, in comparison with H group, the serum concentration of MDA was decreased and DPPHwas increased significantly. Our findings demonstrated that carvacrol decreases hypertrophy markers in in-vivo and in-vitro models of hypertrophy.

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Gupta S, Das B and Sen S. Cardiac hypertrophy:
mechanisms and therapeutic opportunities. Antioxid.
Redox Signal. (2007) 9: 623-52.
Shimizu I and Minamino T. Physiological and
pathological cardiac hypertrophy. J. Mol. Cell.
Cardiol. (2016) 97: 245-62
Katholi RE and Couri DM. Left ventricular hypertrophy:
major risk factor in patients with hypertension: update
and practical clinical applications. Int. J. Hypertens
(2011) 2011: 10.
Takimoto E and Kass DA. Role of oxidative stress in
cardiac hypertrophy and remodeling. Hypertension
(2007) 49: 241-8.
Ceriello A. Possible role of oxidative stress in the
pathogenesis of hypertension. Diabetes Care (2008)
31: S181-S4.
Chen YR and Zweier JL. Cardiac mitochondria and
reactive oxygen species generation. Circ. Res. (2014)
114: 524-37.
Nishino T, Okamoto K, Eger BT, Pai EF and Nishino
T. Mammalian xanthine oxidoreductase–mechanism
of transition from xanthine dehydrogenase to xanthine
oxidase. FEBS J. (2008) 275: 3278-89.
Zhang M, Perino A, Ghigo A, Hirsch E and Shah
AM. NADPH oxidases in heart failure: poachers or
gamekeepers? Antioxid. Redox Signal. (2013) 18:
1024-41.
Amin JK, Xiao L, Pimental DR, Pagano PJ, Singh
K and Sawyer DB. Reactive oxygen species mediate
alpha-adrenergic receptor-stimulated hypertrophy in
adult rat ventricular myocytes. J. Mol. Cell. Cardiol.
(2001) 33: 131-9.
Sawyer DB, Siwik DA, Xiao L, Pimentel DR, Singh K
and Colucci WS. Role of oxidative stress in myocardial
hypertrophy and failure. J. Mol. Cell. Cardiol. (2002)
34: 379-88.
van Empel VP and De Windt LJ. Myocyte hypertrophy
and apoptosis: a balancing act. Cardiovasc. Res.
(2004) 63: 487-99.
Santos MR, Moreira FV, Fraga BP, Souza DPd,
Bonjardim LR and Quintans-Junior LJ. Cardiovascular
effects of monoterpenes: a review. Rev. Bras.
Farmacogn. (2011) 21: 764-71.
Kurkcuoglu M, Tumen G and Baser K. Essential oil
constituents of Satureja boissieri from Turkey. Chem.
Nat. Compd. (2001) 37: 329-31.
Can Baser K. Biological and pharmacological activities
of carvacrol and carvacrol bearing essential oils. Curr.
Pharm. Des. (2008) 14: 3106-19.
Arunasree K. Anti-proliferative effects of carvacrol on
a human metastatic breast cancer cell line, MDA-MB
231. Phytomedicine (2010) 17: 581-8.
Song X, Chen A, Liu Y, Wang X, Zhou Y and Liu
L. Carvacrol pretreatment attenuates myocardial
oxidative stress and apoptosis following myocardial
ischemia-reperfusion in mice. Nan Fang Yi Ke Da Xue
Xue Bao (2013) 33: 24-7.
(1)
(2)
(3)
(4)
(5)
(6)
(7)
(8)
(9)
(10)
(11)
(12)
(13)
(14)
(15)
(16)
Yu W, Liu Q and Zhu S. Carvacrol protects against
acute myocardial infarction of rats via anti-oxidative
and anti-apoptotic pathways. Biol. Pharm. Bull. (2013)
36: 579-84.
Aydin Y, Kutlay O, Ari S, Duman S, Uzuner K and
Aydin S. Hypotensive effects of carvacrol on the blood
pressure of normotensive rats. Planta Med. (2007) 73:
1365-71.
Peixoto‐Neves D, Silva‐Alves K, Gomes M, Lima F,
Lahlou S and Magalhães P. Vasorelaxant effects of the
monoterpenic phenol isomers, carvacrol and thymol,
on rat isolated aorta. Fundam. Clin. Pharmacol.
(2010) 24: 341-50.
Magyar J, Szentandrássy N, Bányász T, Fülöp L,
Varró A and Nánási PP. Effects of terpenoid phenol
derivatives on calcium current in canine and human
ventricular cardiomyocytes. Eur. J. Pharmacol. (2004)
487: 29-36.
Earley S, Gonzales AL and Garcia ZI. A dietary
agonist of transient receptor potential cation channel
V3 elicits endothelium-dependent vasodilation. Mol.
Pharmacol. (2010) 77: 612-20.
Mashhadi FD, Reza JZ, Jamhiri M, Hafizi Z,
Mehrjardi FZ and Safari F. The effect of resveratrol
on angiotensin II levels and the rate of transcription of
its receptors in the rat cardiac hypertrophy model. J.
Physiol. Sci. (2016) 67: 303-9.
Kłapcińska B, Sadowska-Krępa E, Jagsz S, Sobczak
A, Żendzian-Piotrowska M and Górski J. Shortterm effects of electrically induced tachycardia on
antioxidant defenses in the normal and hypertrophied
rat left ventricle. J. Physiol. Sci. (2009) 59: 199-206.
Zhao Z, Yin Y, Wu H, Jiang M, Lou J and Bai G.
Arctigenin, a potential anti-arrhythmic agent, inhibits
aconitine-induced arrhythmia by regulating multi-ion
channels. Cell. Physiol. Biochem. (2013) 32: 1342-53.
Lunec J. Free radicals: their involvement in disease
processes. Ann. Clin. Biochem. (1990) 27: 173-82.
Li Y, Ha T, Gao X, Kelley J, Williams DL and Browder
IW. NF-κB activation is required for the development
of cardiac hypertrophy in vivo. Am. J. Physiol. Heart
Circ. Physiol. (2004) 287: H1712-H20.
Wang Y, Su B, Sah VP, Brown JH, Han J and Chien
KR. Cardiac hypertrophy induced by mitogenactivated protein kinase kinase 7, a specific activator
for c-Jun NH2-terminal kinase in ventricular muscle
cells. J. Biol. Chem. (1998) 273: 5423-6.
Eder P and Molkentin JD. TRPC channels as effectors
of cardiac hypertrophy. Circ. Res. (2011) 108: 265-72.
Guinamard R, Demion M, Magaud C, Potreau D
and Bois P. Functional expression of the TRPM4
cationic current in ventricular cardiomyocytes from
spontaneously hypertensive rats. Hypertension (2006)
48 :587-94.
Bush EW, Hood DB, Papst PJ, Chapo JA, Minobe W
and Bristow MR. Canonical transient receptor potential
channels promote cardiomyocyte hypertrophy through
activation of calcineurin signaling. J. Biol. Chem.
(2006) 281: 33487-96.
(17)
(18)
(19)
(20)
(21)
(22)
(23)
(24)
(25)
(26)
(27)
(28)
(29)
(30)
References
 Jamhiri M et al. / IJPR (2019), 18 (3): 1380-1394
1394
Dantas BPV, Alves QL, de Assis KS, Ribeiro TP, de
Almeida MM and de Vasconcelos AP. Participation of
the TRP channel in the cardiovascular effects induced
by carvacrol in normotensive rat. Vascul. Pharmacol.
(2015) 67: 48-58.
Kim NH and Kang PM. Apoptosis in cardiovascular
diseases: mechanism and clinical implications. Korean
Circ. J. (2010) 40: 299-305.
Yu H, Zhang ZL, Chen J, Pei A, Hua F and Qian X.
Carvacrol, a food-additive, provides neuroprotection
on focal cerebral ischemia/reperfusion injury in mice.
PloS One (2012) 7: e33584.
Chen W, Xu B, Xiao A, Liu L, Fang X and Liu
R. TRPM7 inhibitor carvacrol protects brain from
neonatal hypoxic-ischemic injury. Mol. Brain (2015)
8: 11.
Zhenhua Li JW and Yang X. Functions of
autophagy in pathological cardiac hypertrophy.
Int. J. Biol. Sci. (2015) 11: 672-8.
Nakai A, Yamaguchi O, Takeda T, Higuchi Y,
Hikoso S and Taniike M. The role of autophagy in
cardiomyocytes in the basal state and in response to
hemodynamic stress. Nat. Med. (2007) 13: 619-24.
He H, Liu X, Lv L, Liang H, Leng B and Zhao
(31)
(32)
(33)
(34)
(35)
(36)
(37)
D. Calcineurin suppresses AMPK-dependent
cytoprotective autophagy in cardiomyocytes under
oxidative stress. Cell Death Dis. (2014) 5: e997.
Guimarães AG, Oliveira GF, Melo MS, Cavalcanti SC,
Antoniolli AR and Bonjardim LR. Bioassay‐guided
evaluation of antioxidant and antinociceptive activities
of carvacrol. Basic Clin. Pharmacol. Toxicol. (2010)
107: 949-57.
Canbek M, Uyanoglu M, Bayramoglu G, Senturk
H, Erkasap N and Koken T. Effects of carvacrol
on defects of ischemia-reperfusion in the rat liver.
Phytomedicine (2008) 15: 447-52.
Jayakumar S, Madankumar A, Asokkumar S,
Raghunandhakumar S, Kamaraj S and Divya MGJ.
Potential preventive effect of carvacrol against
diethylnitrosamine-induced hepatocellular carcinoma
in rats. Mol. Cell. Biochem. (2012) 360: 51-60.
Aristatile B, Al‐Numair KS, Al‐Assaf AH, Veeramani
C and Pugalendi KV. Protective effect of carvacrol on
oxidative stress and cellular DNA damage induced by
UVB irradiation in human peripheral lymphocytes. J.
Biochem. Mol. Toxicol. (2015) 29: 497-07.