Tài liệu Báo cáo khoa học: Leptin protects H9c2 rat cardiomyocytes from H2O2-induced apoptosis docx

Leptin protects H9c2 rat cardiomyocytes from

H2O2-induced apoptosis

Megumi Eguchi*, Yuantao Liu*, Eyun-Jung Shin and Gary Sweeney

Department of Biology, York University, Toronto, Canada

The rapid increase in the prevalence of obesity to epi￾demic proportions is a serious concern, as obesity is

associated with the development of many complications

including type 2 diabetes, hypertension and heart failure

[1]. Heart failure is a leading cause of mortality in indus￾trialized countries, and is accompanied by progressive

left ventricular remodeling characterized by hypertro￾phy of the myocytes, impaired vascularization in the

heart, abnormal extracellular matrix composition (fibro￾sis) and elevated cardiomyocyte cell death [2]. However,

in addition to increasing the risk for initial myocardial

infarction, obesity may confer protective effects that

limit cardiac remodeling post-infarction, the so-called

obesity paradox [3]. Necrosis was initially viewed as the

major pathway by which cardiomyocytes are lost during

remodeling; however, research in the past 10–15 years

has indicated that apoptosis has important pathophysio￾logical consequences in the development and progres￾sion of heart failure [4,5]. Indeed, the apoptotic rate is

significantly increased (from 0.001% to 0.08%) in the

failing heart [2].

Adipokines, collectively referring to factors derived

from adipose tissue, have attracted tremendous

research interest in recent years as an important mech￾anistic link between obesity and various associated

complications [6]. The circulating adipokine profile is

altered in obese individuals, and it is now clear that

development of heart failure can be directly influenced

by adipokines [1]. Leptin is the product of the obese

(ob) gene, and its main function is to control appetite

and energy expenditure by acting on the hypothalamus

[7]. There is a positive correlation between circulating

leptin concentration and the body mass of an indiv￾idual. This suggests the existence of leptin resistance in

Keywords

apoptosis; caspase; heart failure; leptin;

mitochondria

Correspondence

G. Sweeney, Department of Biology, York

University, Toronto, M3J 1P3 Canada

Fax: +1 416 736 5698

Tel: +1 416 736 2100 ext. 66635

E-mail: [email protected]

*These authors contributed equally to this

work

(Received 23 January 2008, revised 25

March 2008, accepted 14 April 2008)

doi:10.1111/j.1742-4658.2008.06465.x

Obesity is a known risk factor for induction of myocardial infarction, but,

paradoxically, may also confer a protective effect against subsequent

remodeling leading to heart failure. In this study, we investigated the effect

of leptin, the product of the obese (ob) gene, on cardiomyocyte apoptosis,

a well-characterized component of cardiac remodeling after myocardial

infarction. Exposing H9c2 cells to H2O2 decreased cell viability, and this

was attenuated by pretreating cells with leptin for 1 h, but not 24 h. Leptin

also attenuated the ability of H2O2 to increase phosphatidylserine exposure

and annexin V binding. Further investigation of underlying mechanisms of

leptin’s protective effect demonstrated that the H2O2-induced decrease in

mitochondrial membrane potential (Y) leading to cytochrome c release was

attenuated by leptin pretreatment, and this was associated with reduced

translocation of the pro-apoptotic Bax protein to the mitochondrial mem￾brane. Finally, leptin prevented H2O2-induced increases in caspase-3 cleav￾age and activity, although again 24 h leptin pretreatment did not confer

significant protection. In summary, we have demonstrated that acute leptin

pretreatment mediates anti-apoptotic effects in H9c2 rat cardiomyocytes,

which may be of significance in clarifying the direct impact of leptin on the

heart.

Abbreviations

JC-1, 5,5¢,6,6¢-tetrachloro-1,1¢,3,3¢-tetraethylbenzimidazoyl carbocyanide iodide; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium

bromide; PS, phosphatidylserine.

3136 FEBS Journal 275 (2008) 3136–3144 ª 2008 The Authors Journal compilation ª 2008 FEBS