Gallic acid attenuates calcium calmodulin-dependent kinase
II-induced apoptosis in spontaneously hypertensive rats
a, b, #
, Zhe Hao Piao
, Chun Ping Liu
, Simei Sun
, Bin Liu
, Gwi Ran Kim
Sin Young Choi
, Yuhee Ryu
, Hae Jin Kee
* , Myung Ho Jeong
Heart Research Center of Chonnam National University Hospital, Gwangju, Korea
Jilin Hospital Afﬁliated with Jilin University, Chuanying, Jilin, China
The Second Hospital of Jilin University, Nanguan, Changchun, China
Received: June 2, 2017; Accepted: September 21, 2017
Hypertension causes cardiac hypertrophy and leads to heart failure. Apoptotic cells are common in hypertensive hearts. Ca
dent protein kinase II (CaMKII) is associated with apoptosis. We recently demonstrated that gallic acid reduces nitric oxide synthase inhibition-
induced hypertension. Gallic acid is a trihydroxybenzoic acid and has been shown to have beneﬁcial effects, such as anti-cancer, anti-calciﬁca-
tion and anti-oxidant activity. The purpose of this study was to determine whether gallic acid regulates cardiac hypertrophy and apoptosis in
essential hypertension. Gallic acid signiﬁcantly lowered systolic and diastolic blood pressure in spontaneously hypertensive rats (SHRs). Wheat
germ agglutinin (WGA) and H&E staining revealed that gallic acid reduced cardiac enlargement in SHRs. Gallic acid treatment decreased cardiac
hypertrophy marker genes, including atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), in SHRs. The four isoforms, a, b, d
and c,ofCaMKII were increased in SHRs and were signiﬁcantly reduced by gallic acid administration. Gallic acid reduced cleaved caspase-3
protein as well as bax, p53 and p300 mRNA levels in SHRs. CaMKII d overexpression induced bax and p53 expression, which was attenuated
by gallic acid treatment in H9c2 cells. Gallic acid treatment reduced DNA fragmentation and the TUNEL positive cells induced by angiotensin II.
Taken together, gallic acid could be a novel therapeutic for the treatment of hypertension through suppression of CaMKII d-induced apoptosis.
spontaneously hypertensive rats (SHR)
Hypertension is a major cardiovascular risk factor that leads to
atherosclerosis, cardiac hypertrophy, heart failure and stroke. Sponta-
neously hypertensive rats (SHRs) are a well-established genetic ani-
mal model of hypertension that mimics essential hypertension in
humans . Cardiac hypertrophy is typically present in hypertensive
rats . Hypertension induces left ventricular hypertrophy (LVH),
which is characterized by increased cardiomyocyte size, increased
protein synthesis, activation of foetal gene programmes and reorgani-
zation of sarcomere structure . Hypertension is associated with
myocardial apoptosis, which is a process of programmed cell death.
Increased apoptosis occurs in the heart tissue of SHRs [4, 5]. It was
recently shown that endoplasmic reticulum (ER) stress induces
apoptosis in SHRs . ER stress activates Ca
dent protein kinase II (CaMKII) via several pathways .
CaMKII is involved in the development of pathological cardiac
hypertrophy and heart failure [8, 9]. CaMKII is currently recognized
as a key mediator of cardiovascular disease. CaMKII d and c isoforms
are expressed in the heart , whereas CaMKII a and b isoforms
are expressed in the brain. We recently reported that CaMKII a mRNA
and protein expression are induced in angiotensin II-treated vascular
smooth muscle cells . This implicates CaMKII a as having a role
in hypertension. CaMKII d has two forms, CaMKII d
and CaMKII d
Mice that overexpressed nuclear CaMKII d
were shown to develop
cardiac hypertrophy and dilated cardiomyopathy, whereas transgenic
mice overexpressing cytoplasmic CaMKII d
Both authors contributed equally to this work.
*Correspondence to: Hae Jin KEE, Ph.D.
Myung Ho JEONG, M.D., Ph.D., FACC, FAHA, FESC, FSCAI, FAPSIC
ª 2017 The Authors.
Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.
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J. Cell. Mol. Med. Vol 22, No 3, 2018 pp. 1517-1526