Expression of the angiotensinogen gene and localization of its protein in the human heart.

Sawa, Hirofumi; Tokuchi, Fumio; Mochizuki, Naoki; Endo, Yuka; Furuta, Yoshikazu; Shinohara, Toshiya; Takada, Ayato; Kawaguchi, Hideaki; Yasuda, Hisakazu; Nagashima, Kazuo

doi:10.1161/01.cir.86.1.138

Cited by 65 publications

(31 citation statements)

References 22 publications

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“…Angiotensinogen mRNA has been detected in cardiac tissue homogenates." 12 Are the cardiac Ang I and II levels we measured the true in vivo levels? We took precautions to prevent the ex vivo generation and breakdown of angiotensins.…”

Section: Discussionmentioning

confidence: 99%

“…5 Angiotensinogen mRNA and angiotensinogen have been detected in rat" and human 12 cardiac tissue as well as in cultured myocytes and fibroblasts from neonatal rat hearts. 5 It has also been reported that angiotensinogen is released by the isolated perfused rat Langendorff heart, 13 but it remains to be proved that this angiotensinogen was not derived from plasma.…”

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confidence: 99%

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Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis.

et al. 1994

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The existence of a cardiac renin-angiotensin system, independent of the circulating renin-angiotensin system, is still controversial. We compared the tissue levels of reninangiotensin system components in the heart with the levels in blood plasma in healthy pigs and 30 hours after nephrectomy. Angiotensin I (Ang I)-generating activity of cardiac tissue was identified as renin by its inhibition with a specific active site-directed renin inhibitor. We took precautions to prevent the ex vivo generation and breakdown of cardiac angiotensins and made appropriate corrections for any losses of intact Ang I and II during extraction and assay. Tissue levels of renin (n=ll) and Ang I (n=7) and II (n=7) in the left and right atria were higher than in the corresponding ventricles (P< .05). Cardiac renin and Ang I levels (expressed per gram wet weight) were similar to the plasma levels, and Ang II in cardiac tissue was higher than in plasma (P<.05). The presence of these renin-angiotensin system components in cardiac tissue therefore cannot be accounted for by trapped plasma or simple diffusion from plasma into the interstitial fluid. Angiotensinogen levels (n=ll) in cardiac tissue were 10% to 25% of the A ngiotensin I (Ang I) is produced in the circulating / \ blood by the action of renin from the kidney on -Z A . angiotensinogen produced by the liver. Ang I is converted to Ang II, a potent vasoconstrictor, by angiotensin-converting enzyme (ACE) located on the luminal surface of the vascular endothelium. It is now well established that Ang I and II are not only produced in the blood compartment but also locally in tissues. Recent evidence suggests that complete local reninangiotensin systems (RAS) are present in a number of organs, for instance, kidney, adrenal gland, and ovary. 13In such local RAS, the production of Ang I and II is thought to depend on in situ synthesized renin rather than plasma-derived renin.A local cardiac RAS has also been postulated. 4 ' 5 However, direct evidence for Ang I and II production in the heart by in situ synthesized renin is still lacking. Renin mRNA levels in the heart are usually low and can be detected only by polymerase chain reaction. 68 Early studies showed Ang I-generating activity in left ventric-

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis.

et al. 1994

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“…21 Briefly, the cells or sections were incubated in methanol containing 0.25% H 2 O 2 for 15 minutes. After washing with PBS, they were incubated with normal serum for 30 minutes (horse serum for assay of HHF-35 and RAM-11 and goat serum for assay of PAI-1 antigen, factor Vlll-related antigen, and thrombomodulin), primary antibody (60 minutes), biotinylated second antibody (60 minutes at 37°C), and avidin-biotin peroxidase complexes (30 minutes).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Augmented arterial wall expression of type-1 plasminogen activator inhibitor induced by thrombosis.

Sawa

Fujii

Sobel

1992

Arterioscler Thromb

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Type-1 plasminogen activator inhibitor (PAI-1), the primary physiological inhibitor of endogenous plasminogen activators, modulates fibrinolysis, cell migration, and tissue repair. To determine whether genetic expression of PAI-1 is augmented in the walls of vessels exposed to thrombi but not to a direct physical insult such as electrical injury, we induced arterial thrombosis in rabbit carotid arteries with intraluminal surgical silk sutures and performed in situ hybridization for PAI-1 messenger RNA (mRNA) and immunohistochemistry for PAI-1 antigen at selected intervals. PAI-1 activity in plasma remained virtually constant. In contrast, PAI-1 mRNA increased in endothelial cells juxtaposed to thrombi, in smooth muscle cells adjacent to the neointima, and in macrophages surrounding the suture material. PAI-1 protein was detected in regions in which PAI-1 mRNA was expressed. The increased expression of PAI-1 mRNA colocalized with PAI-1 protein in the endothelium juxtaposed to thrombi may potentiate thrombosis by shifting the local balance between fibrinolysis and thrombosis toward thrombosis. Furthermore, it may alter vascular remodeling and predispose to stenosis after interventions such as angioplasty, in which local thrombosis cannot be avoided.

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“…In both canine and human ventricle, I to density is higher in epicardial and midmyocardial than in the endocardial cells (17,18). The gradient of I to inversely correlates with the gradient of angiotensinogen across the ventricular wall whose expression is more prominent in the subendocardial than in either midmyocardium or epicardium regions (20). Evidence exists that cardiomyocytes, Purkinje fibers, and cardiac fibroblasts produce angiotensin II (21)(22)(23).…”

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confidence: 99%

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

Doronin

Potapova

et al. 2004

Journal of Biological Chemistry

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We report a novel signal transduction complex of the angiotensin receptor type 1. In this complex the angiotensin receptor type 1 associates with the potassium channel ␣-subunit Kv4.3 and regulates its intracellular distribution and gating properties. Electrophysiological remodeling in hypertrophy and heart failure predisposes the heart to lethal arrhythmias, which account for half of the mortality (1, 2). Experimental evidence derived from large scale clinical trials shows that inhibition of angiotensin II synthesis by inhibitors of angiotensin-converting enzyme or direct blockade of angiotensin receptor type 1 (AT1 1 receptor) with the antagonist losartan protects the heart from hypertensive complications (3, 4). A substantial reduction in mortality has been attributed to a significant decrease in sudden cardiac deaths possibly because of fewer episodes of complex arrhythmias (5, 6). The positive influence of inhibition of angiotensin-converting enzyme has been linked to bradykinin-mediated effects (7,8). However, the role of direct blockade of the AT1 receptor by losartan in episodes of sudden cardiac arrhythmias is still debated (9 -11). Electrophysiologic remodeling affects the entire spectrum of cardiac ion channels including the transient outward potassium current (I to ) whose density is often decreased in heart failure (2, 12, 13).The mechanism of I to down-regulation in heart failure is not completely understood and is likely to have multiple etiologies. In part it can be explained by the inhibitory effects of angiotensin II. Experiments with spontaneously hypertensive rats suggest that the AT1 receptor might be directly involved in the regulation of I to . In this animal model I to is inhibited and can be recovered by treatment with the AT1 receptor specific antagonist losartan (14). Experiments with isolated cardiomyocytes show that stimulation of the AT1 receptor results in the inhibition of I to in myocytes from rat or canine ventricle (15,16). In large mammals such as dogs or humans with substantial ventricular wall thickness, I to exhibits a transmural gradient that is vital for normal electrical activity (17,18). Distortion of the I to gradient leads to dispersion of repolarization across the ventricular wall, providing a substrate for ventricular arrhythmias (19). In both canine and human ventricle, I to density is higher in epicardial and midmyocardial than in the endocardial cells (17,18). The gradient of I to inversely correlates with the gradient of angiotensinogen across the ventricular wall whose expression is more prominent in the subendocardial than in either midmyocardium or epicardium regions (20). Evidence exists that cardiomyocytes, Purkinje fibers, and cardiac fibroblasts produce angiotensin II (21-23). Therefore, locally produced angiotensin II could act in a paracrine and/or autocrine manner to regulate I to . Experiments in vitro show that losartan stimulates I to in canine cardiomyocytes isolated from endocardium and converts the configuration of the action potential of endocar...

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Expression of the angiotensinogen gene and localization of its protein in the human heart.

Cited by 65 publications

References 22 publications

Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis.

Cardiac renin and angiotensins. Uptake from plasma versus in situ synthesis.

Augmented arterial wall expression of type-1 plasminogen activator inhibitor induced by thrombosis.

Angiotensin Receptor Type 1 Forms a Complex with the Transient Outward Potassium Channel Kv4.3 and Regulates Its Gating Properties and Intracellular Localization

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