Study on the preventive and therapeutic effects of grape seed proanthocyanidin extract on doxorubicin-induced chronic cardiotoxicity

doi:10.11958/20252608

Abstract

Abstract:

Objective To investigate the effect of grape seed proanthocyanidin extract (GSPE) on doxorubicin-induced chronic cardiotoxicity by regulating the nuclear factor E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathway. Methods Thirty-six 6-week-old SD rats were randomly divided into six groups (n=6 for each group): the control group (control), the doxorubicin group (DOX), the doxorubicin+low-dose GSPE group (L-GSPE), the doxorubicin+medium-dose GSPE group (M-GSPE), the doxorubicin+ high-dose GSPE group (H-GSPE) and the doxorubicin+tert-butylhydroquinone group (TBHQ). Except for the control group, rats in the other groups were injected intraperitoneally with doxorubicin (2.5 mg/kg) once weekly for 6 consecutive weeks to establish the chronic cardiotoxicity model. The control group received equal volume of intraperitoneal injection of 0.9% NaCl solution (1 mL/kg). Starting from the first day of doxorubicin injection, the L-GSPE, M-GSPE and H-GSPE groups were administered GSPE solutions at doses of 100 mg/kg, 200 mg/kg and 400 mg/kg, respectively, via oral gavage. The TBHQ group was given 25 mg/kg TBHQ solution, while the control group and the DOX group were given an equal volume of ddH₂O. Cardiac structure and function were evaluated using echocardiography. Cardiac tissue morphology and fibrosis were observed via HE and Masson staining. Serum levels of superoxide dismutase (SOD), malondialdehyde (MDA), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), cardiac troponin T (cTnT) and brain natriuretic peptide (BNP) were measured using commercial kits and ELISA. Western blot assay and qRT-PCR were employed to assess protein and mRNA expression levels of Nrf2, NAD(P)H quinone oxidoreductase 1 (NQO1) and HO-1 in cardiac tissue. Results Compared with the DOX group, the cardiac structure and function, myocardial injury and fibrosis were all improved in the GSPE-treated groups, serum levels of TNF-α, IL-6, MDA, cTnT and BNP decreased, and serum SOD activity, protein and mRNA expression levels of Nrf2, HO-1 and NQO1 increased. Notably, the H-GSPE group demonstrated more significant improvement compared to the L-GSPE group (P<0.05). Conclusion GSPE may exert preventive and therapeutic effects against doxorubicin-induced chronic cardiotoxicity by activating the Nrf2/HO-1 signaling pathway.

Key words: doxorubicin, cardiotoxicity, heme oxygenase-1, grape seed proanthocyanidin extract, Nrf2 signaling pathway

CLC Number:

R541

Figures/Tables 9

References 23

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基因名称	引物序列（5′→3′）	产物大小/bp
Nrf2	上游：TCCATTTACGGAGACCCAC	106
	下游：GTGTTGGCTGTGCTTTAGGT	106
HO-1	上游：AGCGAAACAAGCAGAACC	191
	下游：CAGCAGCTCAGGATGAGTAC	191
NQO1	上游：GAAGGGTGGAAGAAGCGT	292
	下游：TGGAACAAAGGCGAAAACT	292
GAPDH	上游：CAAGTTCAACGGCACAG	138
	下游：CCAGTAGACTCCACGACAT	138

基因名称	引物序列（5′→3′）	产物大小/bp
Nrf2	上游：TCCATTTACGGAGACCCAC	106
	下游：GTGTTGGCTGTGCTTTAGGT	106
HO-1	上游：AGCGAAACAAGCAGAACC	191
	下游：CAGCAGCTCAGGATGAGTAC	191
NQO1	上游：GAAGGGTGGAAGAAGCGT	292
	下游：TGGAACAAAGGCGAAAACT	292
GAPDH	上游：CAAGTTCAACGGCACAG	138
	下游：CCAGTAGACTCCACGACAT	138

组别	LVEDD/mm	LVESD/mm	LVEDV/mL
Control组	4.22±0.87	2.43±0.14	0.32±0.08
DOX组	6.40±0.24^a	3.38±0.14^a	0.55±0.05^a
L-GSPE组	5.76±0.43^a	3.21±0.15^a	0.42±0.34^b
M-GSPE组	4.98±0.60^b	2.91±0.16^ab	0.37±0.08^b
H-GSPE组	4.67±0.18^bc	2.69±0.48^bc	0.36±0.03^b
TBHQ组	5.46±0.22	3.10±0.16^a	0.41±0.29^b
F	7.736^＊＊	6.548^＊＊	5.996^＊＊
组别	LVESV/mL	LVEF	LVFS
Control组	0.06±0.03	0.82±0.01	0.45±0.02
DOX组	0.13±0.01^a	0.56±0.05^a	0.33±0.02^a
L-GSPE组	0.10±0.02	0.65±0.03^ab	0.35±0.04^a
M-GSPE组	0.10±0.03	0.75±0.03^abc	0.40±0.01^abc
H-GSPE组	0.08±0.02^b	0.80±0.02^bc	0.42±0.02^bc
TBHQ组	0.10±0.02	0.71±0.01^abc	0.34±0.03^a
F	2.145	36.999^＊＊	21.478^＊＊

组别	LVEDD/mm	LVESD/mm	LVEDV/mL
Control组	4.22±0.87	2.43±0.14	0.32±0.08
DOX组	6.40±0.24^a	3.38±0.14^a	0.55±0.05^a
L-GSPE组	5.76±0.43^a	3.21±0.15^a	0.42±0.34^b
M-GSPE组	4.98±0.60^b	2.91±0.16^ab	0.37±0.08^b
H-GSPE组	4.67±0.18^bc	2.69±0.48^bc	0.36±0.03^b
TBHQ组	5.46±0.22	3.10±0.16^a	0.41±0.29^b
F	7.736^＊＊	6.548^＊＊	5.996^＊＊
组别	LVESV/mL	LVEF	LVFS
Control组	0.06±0.03	0.82±0.01	0.45±0.02
DOX组	0.13±0.01^a	0.56±0.05^a	0.33±0.02^a
L-GSPE组	0.10±0.02	0.65±0.03^ab	0.35±0.04^a
M-GSPE组	0.10±0.03	0.75±0.03^abc	0.40±0.01^abc
H-GSPE组	0.08±0.02^b	0.80±0.02^bc	0.42±0.02^bc
TBHQ组	0.10±0.02	0.71±0.01^abc	0.34±0.03^a
F	2.145	36.999^＊＊	21.478^＊＊

组别	MDA/ （μmol/L）	SOD/ （U/mL）	cTnT/ （ng/L）	BNP/ （ng/L）
Control组	5.49±0.68	52.66±3.85	53.37±4.79	678.21±122.68
DOX组	11.65±0.35^a	24.70±1.00^a	131.58±16.76^a	1 629.78±43.77^a
L-GSPE组	8.90±0.57^ab	28.21±2.03^ab	98.61±4.11^ab	1 369.97±137.91^ab
M-GSPE组	8.33±0.75^abc	33.48±1.19^abc	82.88±8.57^abc	1 243.06±119.51^abc
H-GSPE组	6.41±0.85^abc	42.23±2.09^abc	74.56±5.06^abc	1 048.78±94.94^abc
TBHQ组	7.71±1.20^abc	37.51±1.25^bc	81.46±6.09^abc	1 107.62±97.37^abc
F	136.564^＊＊	404.964^＊＊	163.411^＊＊	162.285^＊＊