期刊
JOURNAL OF THE AMERICAN HEART ASSOCIATION
卷 3, 期 2, 页码 -出版社
WILEY
DOI: 10.1161/JAHA.114.000874
关键词
animal model; chemokine; diastolic function; echocardiography; HIV
资金
- NIH [HL078479, P40 OD013117, T32 OD011089]
- American College of Veterinary Pathologists/Society of Toxicologic Pathology Coalition for Veterinary Pathology Fellows (Merck)
- International Society for Heart Research-European Section/Servier
Background-Diastolic dysfunction is a highly prevalent cardiac abnormality in asymptomatic as well as ART-treated human immunodeficiency virus (HIV) patients. Although the mechanisms underlying depressed cardiac function remain obscure, diastolic dysfunction in SIV-infected rhesus macaques is highly correlated with myocardial viral load. As cardiomyocytes are not productively infected, damage may be an indirect process attributable to a combination of pro-inflammatory mediators and viral proteins. Methods and Results-Given the diverse roles of CCR5 in mediating recruitment of leukocytes to inflammatory sites and serving as a receptor for HIV entry into cells, we investigated the role of CCR5 in the SIV/macaque model of diastolic dysfunction. We found that in SIV-infected macaques, CCR5 inhibition dramatically impacted myocardial viral load measured by qRT-PCR and prevented diastolic dysfunction measured by echocardiography. Complementary in vitro experiments using fluorescence microscopy showed that CCR5 ligands impaired contractile function of isolated cardiomyocytes, thus identifying CCR5 signaling as a novel mediator of impaired cardiac mechanical function. Conclusions-Together, these findings incriminate SIV/HIV gp120-CCR5 as well as chemokine-CCR5 interactions in HIV-associated cardiac dysfunction. These findings also have important implications for the treatment of HIV-infected individuals: in addition to antiviral properties and reduced chemokine-mediated recruitment and activation of inflammatory cells, CCR5 inhibition may provide a cardioprotective benefit by preventing cardiomyocyte CCR5 signaling.
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