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C42 JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, VOL. 70, NO.

16, SUPPL C, 2017

pathway activity, and inhibiting the proliferation and migration of related to the pathogenesis of heart failure with preserved ejection
VSMCs after vascular injury. fraction (HFpEF).
METHODS 3-month-old and 12-month-old SHRs (n¼3 for each) were
GW28-e1064 subjected to echocardiographic study, histopathological analysis,
Qiliqiangxin protects against cardiac diastolic dysfunction and CD31 immunohistochemical staining and dihydroethidium (DHE)
ameliorates myocardial glucose metabolism in spontaneously staining. Subsequently, small RNA sequencing and data processing
hypertensive rats was executed to identify differentially expressed miRNAs between
these two groups. Eight significantly up-regulated miRNAs were
Jingfeng Wang,1 Zhiming Li,2 Jingmin Zhou,1 Junbo Ge1 validated by real-time quantitative reverse transcription-polymerase
1
Department of Cardiology, Zhongshan Hospital, Fudan University, chain reaction(qRT-PCR), followed by in silico target genes prediction.
Shanghai, China; 2Department of Cardiology, People’s Hospital of Functional annotation analysis of the predicted targets were per-
Nanbu County, Nanchong, Sichuan, China formed by Gene Ontology and KEGG databases.

OBJECTIVES Cardiac diastolic dysfunction has emerged as a growing RESULTS Compared with 3-month-old SHRs, a significantly impaired
type of heart failure. The present study aims to explore whether left ventricular diastolic function was observed in 12-month-old SHRs
Qiliqiangxin (QL) can benefit cardiac diastolic function in spontane- with declined E/A ratio (1.720.23 vs. 2.250.07, p<0.05), E’/A’ ratio
ously hypertensive rats (SHRs) through enhancement of cardiac (0.780.02 vs. 1.640.26, p<0.01) and increased E/E’ (38.22.0 vs.
glucose metabolism. 26.02.5, p<0.01). Histological studies revealed significantly
increased myocyte cross-sectional area (864.069.1mm 2 vs.
METHODS Fifteen 12-month-old male SHRs were randomly divided 461.740.4mm 2, p<0.01), higher percentage of fibrosis area (10.41.3%
into QL-treated (0.5g/kg$d), olmesartan-treated (2.5mg/kg$d) and sa- vs.7.11.1%, p<0.05), increased reactive oxygen species (ROS) pro-
line-treated groups. Age-matched WKY rats served as normal controls. duction (DHE fluorescent intensity 0.0550.009 vs. 0.0450.004,
Systolic blood pressure and echocardiographic evaluation were car- p<0.05), and reduced microvessels density (14.23.3 vs. 26.34.9,
ried out before and 8 weeks after drug administration. Myocardial p<0.01) in hearts of 12-month-old SHRs. Compared with 3-month-old
glucose uptake was determined by 18F-FDG using small-animal posi- SHRs, 21 miRNAs were significantly up-regulated and 5 miRNAs were
tron emission tomography (PET) imaging with standardized uptake down-regulated in 12-month-old ones (p<0.05). qRT-PCR results were
value (SUV) calculated. After euthanasia, plasma NT-proBNP, TNF-a, consistent with small RNA sequencing data on eight up-regulated
TGF-b1 and histopathological changes were assessed. Protein expres- miRNAs, including rno-miR-132-3p, rno-miR-182, rno-miR-208b-3p,
sions of GLUT-1, GLUT-4, phospho-AMPKa, PGC-1a, together with rno-miR-212-3p, rno-miR-214-3p, rno-miR-218a-5p, rno-miR-221-3p
myocardial ATP content and citrate synthase (CS) activity were eval- and rno-miR-222-3p, which were submitted to bioinformatics anal-
uated. Gene expressions of hexokinase-2 (HK2), pyruvate dehydro- ysis. Target genes were significantly enriched in 688 GO terms and 39
genase kinase-4 (PDK4) and CS were also detected. KEGG pathways, including regulation of peptidyltyrosine phos-
RESULTS SHRs exhibited left ventricular diastolic dysfunction, car- phorylation, regulation of protein serine/threonine kinase activity,
diac hypertrophy, fibrosis and apoptosis, and impaired myocardial adrenergic signaling in cardiomyocytes, ErbB signaling pathway,
glucose metabolism compared with WKY rats. QL improved cardiac mTOR signaling pathway, FoxO signaling pathway, Ras signaling
diastolic function, as evidenced by increased E’/A’ (1.210.16 vs. pathway, insulin secretion, adipocytokine signaling pathway, HIF-1
0.870.17, p<0.01) and decreased E/E’ (23.432.23 vs. 31.304.23, signaling pathway, Rap1 signaling pathway, VEGF signaling pathway,
p<0.01), which were independent of systolic blood pressure. QL chemokine signaling pathway, TNF signaling pathway, etc.
significantly decreased plasma levels of NT-proBNP (192.342.5pg/ml CONCLUSIONS Our data reported a dysregulated miRNA profile in
vs. 337.864.9pg/ml, p<0.01), TNF-a (72.97.4pg/ml vs. 86.88.9pg/ aging SHRs, indicating the critical role of miRNAs in the process of
ml, p<0.05) and TGF-b1 (19.42.6ng/ml vs. 23.33.5 ng/ml, p<0.01), HFpEF. Target genes of these differentially expressed miRNAs were
which were markedly higher in saline-treated SHRs. Meanwhile, QL involved in multiple signaling pathways associated with cardiac hy-
alleviated myocardial hypertrophy, collagen deposits and apoptosis in pertrophy, autophagy, insulin metabolism, angiogenesis and inflam-
SHRs, as exhibited by decreased cardiomyocyte cross-sectional area matory response.
(613.466.8mm2 vs. 760.663.3mm 2, p<0.01), reduced percentage of
fibrotic deposits(6.960.77% vs. 12.701.38%, p<0.01), and fewer
TUNEL positive cells(13.762.31 vs. 23.305.94, p<0.01). Compared GW28-e1067
with age-matched WKY rats, PET acquisition showed an increase in Urotensin II induces endothelial-mesenchymal transition of
myocardial 18F-FDG uptake in SHRs(4.940.51 vs. 2.940.39, p<0.01); cardiac microvascular endothelial cells via endoplasmic
while an even higher myocardial glucose uptake was illustrated in QL- reticulum stress
treated SHR group (7.100.72 vs. 4.940.51, p<0.01). Moreover, QL- Yonggang Zhang,1,2 Jinyao Zhong,1 Yuqiang Cui,1 Da Chen,1 Lihua Ji,1
treated animals revealed a significantly higher myocardial CS activity Fan Zheng,1 Xiaoying Zheng,1 Wenbin Xia1
(1307.7125.5nmol/min/mg vs. 932.569.5nmol/min/mg, p<0.05) and 1
Department of Cardiology, Second Affiliated Hospital, Shantou
ATP production (26.82.9 mmol/mg vs. 17.34.0 mmol/mg, p<0.01) University Medical College; 2Laboratory of Cardiology, Centre for
than SHR control. Western blotting exhibited a significantly increased Translational Medicine, Shantou University Medical College
GLUT-4, phospho-AMPKaThr172, PGC-1a and decreased GLUT-1
expression in QL-treated SHRs in comparison to SHR control (p<0.01). OBJECTIVES Recent studies suggest that endothelial-mesenchymal
qRT-PCR results showed that QL significantly upregulated mRNA ex- transition (EndMT) as a link between endoplasmic reticulum stress
pressions of HK2 and CS, and downregulated PDK4 expression (ER stress) and fibrosis. We previous found that urotensin II (UII)
(p<0.01). Olmesartan also demonstrated beneficial effects on cardiac could promote EndMT in cardiac microvascular endothelial cells of
diastolic function and glucose metabolism. rats. Therefore, in the present study, we explored the effect of UII on
CONCLUSIONS Our data suggests that QL improves cardiac diastolic the induction of ER stress, and whether ER stress could mediate the
function and inhibits myocardial hypertrophy, fibrosis and apoptosis UII-induced EndMT.
in SHRs, which may be associated with enhancement of myocardial METHODS Growth-arrested cardiac microvascular endothelial cells
glucose uptake, utilization and oxidative phosphorylation. from neonatal rats were incubated in serum-free medium with UII.
Markers of ER stress (GRP78, CHOP) and EndMT (a-SMA, VE-cad-
GW28-e1065 herin), and type I collagen were detected by western blot and /or real
Investigation of differentially expressed microRNAs between time PCR, respectively.
young and aging spontaneously hypertensive rats based on RESULTS UII induced GRP78 protein expression in a time-dependent
bioinformatics analysis manner, with maximal effect at 48h (94.3%). It also caused a dose-
Jingfeng Wang,1 Jingjing Zhang,2 Jingmin Zhou,1 Junbo Ge1 dependent manner in GRP78 expression, with maximal effect at a
1
Department of Cardiology, Zhongshan Hospital, Fudan University, concentration of 10-7mol/l (148.3%). In addition, UII significantly
Shanghai, China; 2Department of Cardiology, Shandong University, induced CHOP protein expression, upregulated a-SMA protein and
Jinan, Shandong, China Pro- collagen I mRNA and protein expression, while downregulated
VE-cadherin expression. The UII effects were significantly reversed by
OBJECTIVES MicroRNA (miRNA, miR) serves as an important regu- sodium 4-phenylbutyrate (4-PBA, 510-4mol/l), an inhibitor of ER
lator in cardiac hypertrophy. The present study aims to investigate the Stress, as well as urantide (10-6mol/l), an antagonist of UII receptor.
differential expression profile of miRNAs between young and aging CONCLUSIONS This study indicated that, ER stress is involved in the UII-
spontaneously hypertensive rats (SHRs) and how these profiles are induced EndMT, which might be a new mechanism of cardiac fibrosis.

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