TY - JOUR
T1 - Xanthine oxidase inhibitor allopurinol prevents oxidative stress-mediated atrial remodeling in alloxan-induced diabetes mellitus rabbits
AU - Yang, Yajuan
AU - Zhao, Jianping
AU - Qiu, Jiuchun
AU - Li, Jian
AU - Liang, Xue
AU - Zhang, Zhiwei
AU - Zhang, Xiaowei
AU - Fu, Huaying
AU - Korantzopoulos, Panagiotis
AU - Letsas, Konstantinos P.
AU - Tse, Gary
AU - Li, Guangping
AU - Liu, Tong
N1 - Publisher Copyright:
© 2018 The Authors.
PY - 2018/5/15
Y1 - 2018/5/15
N2 - Background--There are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes. Methods and Results--Ninety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol-treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage-clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial-related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment. Conclusions--Allopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM-related increases in oxidative stress.
AB - Background--There are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes. Methods and Results--Ninety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol-treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage-clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial-related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment. Conclusions--Allopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM-related increases in oxidative stress.
KW - Allopurinol
KW - Atrial fibrillation
KW - Calcium signaling
KW - Diabetes mellitus
KW - Mitochondria
KW - Oxidative stress
KW - Xanthine oxidase
UR - http://www.scopus.com/inward/record.url?scp=85046950081&partnerID=8YFLogxK
U2 - 10.1161/JAHA.118.008807
DO - 10.1161/JAHA.118.008807
M3 - Article
C2 - 29720500
AN - SCOPUS:85046950081
VL - 7
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 10
M1 - e008807
ER -