Tumor necrosis factor-alpha produced in cardiomyocytes mediates a predominant myocardial inflammatory response to stretch in early volume overload.
Acute stretch caused by volume overload (VO) of aorto-caval fistula (ACF) induces a variety of myocardial responses including mast cell accumulation, matrix metalloproteinase (MMP) activation, and collagen degradation, all of which are critical in dictating long-term left ventricle (LV) outcome to VO. Meanwhile, these responses can be part of myocardial inflammation dictated by tumor necrosis factor-alpha (TNF-alpha), which is elevated after acute ACF. However, it is unknown whether TNF-alpha mediates a major myocardial inflammatory response to stretch in early VO. In 24-h ACF and sham rats, microarray gene expression profiling and subsequent Ingenuity Pathway Analysis identified a predominant inflammatory response and a gene network of biologically interactive genes strongly linked to TNF-alpha. Western blot demonstrated increased local production of TNF-alpha in the LV (1.71- and 1.66-fold in pro- and active-TNF-alpha over control, respectively, P<0.05) and cardiomyocytes (2- and 4-fold in pro- and active-TNF-alpha over control, respectively, P<0.05). TNF-alpha neutralization with infliximab (5.5 mg/kg) attenuated the myocardial inflammatory response to acute VO, as indicated by inhibition of inflammatory gene upregulation, myocardial infiltration (total CD45+ cells, mast cells, and neutrophils), MMP-2 activation, collagen degradation, and cardiac cell apoptosis, without improving LV remodeling and function. These results indicate that TNF-alpha produced by cardiomyocytes mediates a predominant inflammatory response to stretch in the early VO in the ACF rat, suggesting an important role of TNF-alpha in initiating pathophysiological response of myocardium to VO.
Chen
Yuanwen
Y
Xinhua Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Pat
Betty
B
Zheng
Junying
J
Cain
Laura
L
Powell
Pamela
P
Shi
Ke
K
Sabri
Abdelkarim
A
Husain
Ahsan
A
Dell'italia
Louis J
LJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D006321:Heart; D008407:Mast Cells / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D009205:Myocarditis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009206:Myocardium / Q000737:chemistry* / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D051381:Rats; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects; D020257:Ventricular Remodeling / Q000235:genetics / Q000502:physiology
D014409:Tumor Necrosis Factor-alpha; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2