The peptide angiotensin II is the effector molecule of the reninangiotensin system. All the haemodynamic effects of angiotensin II, including vasoconstriction and adrenal aldosterone release, are mediated through a single class of cell-surface receptors known as AT1 (refs 1, 2). These receptors contain the structural features of the G-protein-coupled receptor superfamily. We show here that angiotensin II induces the rapid phosphorylation of tyrosine in the intracellular kinases Jak2 and Tyk2 in rat aortic smooth-muscle cells and that this phosphorylation is associated with increased activity of Jak2. The Jak family substrates STAT1 and STAT2 (for signal transducers and activators of transcription) are rapidly tyrosine-phosphorylated in response to angiotensin II. We also find that Jak2 co-precipitates with the AT1 receptor, indicating that G-protein-coupled receptors may be able to signal through the intracellular phosphorylation pathways used by cytokine receptors.

Abstract-The transcription factor signal transducer and activator of transcription 3 (STAT3) participates in a wide variety of physiological processes and directs seemingly contradictory responses such as proliferation and apoptosis. To elucidate its role in the heart, we generated mice harboring a cardiomyocyte-restricted knockout of STAT3 using Cre/loxP-mediated recombination. STAT3-deficient mice developed reduced myocardial capillary density and increased interstitial fibrosis within the first 4 postnatal months, followed by dilated cardiomyopathy with impaired cardiac function and premature death. Conditioned medium from STAT3-deficient cardiomyocytes inhibited endothelial cell proliferation and increased fibroblast proliferation, suggesting the presence of paracrine factors attenuating angiogenesis and promoting fibrosis in vitro. STAT3-deficient mice showed enhanced susceptibility to myocardial ischemia/reperfusion injury and infarction with increased cardiac apoptosis, increased infarct sizes, and reduced cardiac function and survival. Our study establishes a novel role for STAT3 in controlling paracrine circuits in the heart essential for postnatal capillary vasculature maintenance, interstitial matrix deposition balance, and protection from ischemic injury and heart failure. Key Words: mouse Ⅲ signal transduction Ⅲ angiogenesis Ⅲ ischemia Ⅲ heart failure A ctivation of signal transducer and activator of transcription 3 (STAT3) in the heart has been observed in acute myocardial infarction (MI), ischemic preconditioning, and pressure overload. [1][2][3] In this regard, activation of the stressresponsive Janus kinase (JAK)-STAT signaling pathway during ischemia/reperfusion (I/R) injury and MI has been proposed to provide protection against ischemic stress via transcriptional activation of cytoprotective genes. 1,4 Cell culture studies have ascribed some of the cytoprotective actions of the JAK-STAT pathway in cardiomyocytes specifically to STAT3 activation. 5 However, although STAT3 activation is clearly associated with an upregulation of a wide array of target genes in cardiomyocytes, it is unclear which of the reported cardiac responses associated with STAT3 activation are indeed required in vivo for controlling cardiac growth, function, tissue architecture, or protection against cardiovascular stress such as ischemic injury. Importantly, although increased circulating levels of interleukin (IL)-6 -related cytokines predict mortality in patients with heart failure and may enhance gp130 activation in the failing human heart, expression and phosphorylation levels of STAT3 are severely depressed in myocardium obtained from patients with dilated cardiomyopathy, 6 raising the possibility that decreased STAT3 activation may contribute to development of cardiac failure in patients.To elucidate the potential role of STAT3 in cardiac muscle and, in particular, for cardiac protection against physiological and pathophysiological stress, we created mice with a cardiomyocyte-restricted STAT3 deletion. Materials and...

Background-Patients with an activated renin-angiotensin system (RAS) or genetic alterations of the RAS are at increased risk of myocardial infarction (MI). Administration of ACE inhibitors reduces the risk of MI, and acute coronary syndromes are associated with increased interleukin 6 (IL-6) serum levels. Accordingly, the present study evaluated the expression of angiotensin II (Ang II) in human coronary atherosclerotic plaques and its influence on IL-6 expression in patients with coronary artery disease. Methods and Results-Immunohistochemical colocalization of Ang II, ACE, Ang II type 1 (AT 1 ) receptor, and IL-6 was examined in coronary arteries from patients with ischemic or dilated cardiomyopathy undergoing heart transplantation (nϭ12), in atherectomy samples from patients with unstable angina (culprit lesion; nϭ8), and in ruptured coronary arteries from patients who died of MI (nϭ13). Synthesis and release of IL-6 was investigated in smooth muscle cells and macrophages after Ang II stimulation. Colocalization of ACE, Ang II, AT 1 receptor, and IL-6 with CD68-positive macrophages was observed at the shoulder region of coronary atherosclerotic plaques and in atherectomy tissue of patients with unstable angina. Ang II was identified in close proximity to the presumed rupture site of human coronary arteries in acute MI. Ang II induced synthesis and release of IL-6 shortly after stimulation in vitro in macrophages and rat smooth muscle cells. Conclusions-Ang II, AT 1 receptor, and ACE are expressed at strategic sites of human atherosclerotic coronary arteries, suggesting that Ang II is produced primarily by ACE within coronary plaques. The observation that Ang II induces IL-6 and their colocalization with the AT 1 receptor and ACE is consistent with the notion that the RAS may contribute to inflammatory processes within the vascular wall and to the development of acute coronary syndromes. (Circulation. 2000;101:1372-1378.)Key Words: interleukins Ⅲ angiotensin Ⅲ angina Ⅲ myocardial infarction Ⅲ arteries Ⅲ receptors R upture of atherosclerotic plaques occurs predominantly at the edges of the plaque's fibrous cap, the shoulder region, that is, areas of accumulated inflammatory cells, for example, macrophages, T-lymphocytes, and mast cells in close proximity to vascular smooth muscle cells (SMC). [1][2][3][4][5][6] The activated inflammatory cells stimulate their neighboring cells to erode the extracellular matrix through the release of inflammatory cytokines. The decay of the framework that forms the plaque cap leads to plaque rupture 1,7,8 and resembles the morphological correlate of an acute coronary syndrome. Serum levels of interleukin 6 (IL-6) are increased in patients with unstable angina 9 and may trigger the onset of an acute coronary syndrome. 10 IL-6 is known to be involved in the stimulation of matrix-degrading enzymes, for example, metalloproteinases. 11In parallel, the renin-angiotensin system (RAS) has been suggested to be involved in the development of acute coronary syndromes, based on the observat...

Abstract-Angiotensin II type 1 (AT 1 ) receptor activation as well as proinflammatory cytokines such as interleukin-6 (IL-6) are involved in the development and progression of atherosclerosis. The detailed underlying mechanisms including interactions between inflammatory agonists and the renin-angiotensin system are poorly understood. Stimulation of cultured rat aortic vascular smooth muscle cells (VSMCs) with IL-6 led to upregulation of AT 1 receptor mRNA and protein expression, as assessed by Northern and Western blot experiments. Nuclear run-on and transcription blockade experiments showed that IL-6 increases AT 1 receptor mRNA de novo synthesis but not mRNA stability. Preincubation of VSMCs with IL-6 resulted in an enhanced angiotensin II-induced production of reactive oxygen species, as assessed by DCF fluorescence laser microscopy. Treatment of C57BL/6J mice with IL-6 for 18 days increased vascular AT 1 receptor expression (real-time RT-PCR) and angiotensin II-induced vasoconstriction, enhanced vascular superoxide production (L-012 chemiluminescence, DHE fluorescence), and impaired endothelium-dependent vasodilatation. These effects were completely omitted in AT 1 receptor knockout mice (AT1A Ϫ/Ϫ mice). Upregulation of vascular AT 1 receptor expression in vitro and in vivo is decisively involved in IL-6 -induced propagation of oxidative stress and endothelial dysfunction. This interaction of the proinflammatory cytokine IL-6 with the renin-angiotensin system may represent an important pathogenetic mechanism in the atherosclerotic process.