Canine ventricular myocytes possess a renin-angiotensin system that is upregulated with heart failure

被引:101
作者
Barlucchi, L
Leri, A
Dostal, DE
Fiordaliso, F
Tada, H
Hintze, TH
Kajstura, J
Nadal-Ginard, B
Anversa, P
机构
[1] New York Med Coll, Dept Med, Valhalla, NY 10595 USA
[2] New York Med Coll, Dept Physiol, Valhalla, NY 10595 USA
[3] Texas A&M Univ, Div Mol Cardiol, Temple, TX USA
[4] Ist Ric Farmacol Mario Negri, Milan, Italy
关键词
pacing; myocyte renin-angiotensin system; p53; function; heart failure;
D O I
10.1161/01.RES.88.3.298
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Ventricular pacing leads to a dilated myopathy in which cell death and myocyte hypertrophy predominate. Because angiotensin II (Ang II) stimulates myocyte growth and triggers apoptosis, we tested whether canine myocytes express the components of the renin-angiotensin system (RAS) and whether the local RAS is upregulated with heart failure. p53 modulates transcription of angiotensinogen (Aogen) and AT(1) receptors in myocytes, raising the possibility that enhanced p53 function in the decompensated heart potentiates Ang II synthesis and Ang II-mediated responses. Therefore, the presence of mRNA transcripts for Aogen, renin, angiotensin-converting enzyme, chymase, and AT(1) and AT(2) receptors was evaluated by reverse transcriptase-polymerase chain reaction in myocytes, Changes in the protein expression of these genes were then determined by Western blot in myocytes from control dogs and dogs affected by congestive heart failure. p53 binding to the promoter of Aogen and AT(1) receptor was also determined. Ang II in myocytes was measured by ELISA and by immunocytochemistry and confocal microscopy, Myocytes expressed mRNAs for all the constituents of RAS, and heart failure was characterized by increased p53 DNA binding to Aogen and AT(1). Additionally, protein levels of Aogen, renin, cathepsin D, angiotensin-converting enzyme, and AT(1) were markedly increased in paced myocytes, Conversely, chymase and AT(2) proteins were not altered. Ang II quantity and labeling of myocytes increased significantly with cardiac decompensation. In conclusion, dog myocytes synthesize Ang II, and activation of p53 function with ventricular pacing upregulates the myocyte RAS and the generation and secretion of Ang II. Ang II may promote myocyte growth and death, contributing to the development of heart failure.
引用
收藏
页码:298 / 304
页数:7
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