Changes in cardiac ANG II postmyocardial infarction  in rats: effects of nephrectomy and ACE inhibitors

Leenen, Frans H. H.; Skarda, Vaclav; Yuan, Baoxue; White, Roselyn

doi:10.1152/ajpheart.1999.276.1.h317

Cited by 51 publications

(44 citation statements)

References 26 publications

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“…MI was induced by ligation of the left ascending coronary artery (LAD) as described previously (11)(12)(13). In short, after left-sided thoracotomy, the left coronary artery was occluded 2 to 5 mm from its origin with a 6.0 silk suture.…”

Section: Surgical Proceduresmentioning

confidence: 99%

Myocardial Infarction Enhances Progressive Renal Damage in an Experimental Model for Cardio-Renal Interaction

Dokkum¹,

Eijkelkamp²,

Kluppel³

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Studied were the effects of myocardial infarction (MI) on mild renal function loss in unilateral nephrectomized (UnX) rats. UnX was performed, followed after 1 wk by a variable MI (UnX ϩ MI; n ϭ 24). Rats with only UnX (n ϭ 15) or MI (n ϭ 9) and double sham animals (CON, n ϭ 15) served as controls. Renal outcome was measured by proteinuria and plasma creatinine. Focal glomerulosclerosis (FGS) incidence was evaluated by renal histology. Cardiac function and systolic BP were measured. A division into small and large infarcts after UnX was made a priori, resulting in two groups, one with a mild MI (Ͻ20%; n ϭ 15) and one with a moderate MI (Ͼ20%; n ϭ 9). Mild proteinuria up to 55.5 mg/d was observed in the UnX ϩ mild MI group, whereas proteinuria rose significantly higher to 124.5 mg/d in the UnX ϩ moderate MI group. Incidence of FGS was significantly increased in both UnX ϩ MI groups compared with all other groups. The average MI size was 18%, 17%, and 25% in the MI, UnX ϩ mild MI, and UnX ϩ moderate MI group, respectively. LVP in both UnX ϩ MI groups was correlated with proteinuria, indicative of a cardio-renal interaction. Clinically, these data imply that more patients are at risk for cardiovascular events and that after such an event, their chance of more renal function loss increases. Finding the underlying mechanism will enable improved protection for both kidneys and heart. Recent data from clinical studies have fueled the interest in the interaction between kidney and heart, and in particular the interaction between progressive function loss of both organs. The effect of renal impairment on cardiovascular function has been demonstrated in various studies. Patients with mild to severe renal insufficiency, including those patients starting renal replacement therapy, show an increased prevalence of cardiovascular disease (1-3), and Mann et al. (4) showed that impaired renal function increases the risk of cardiovascular events in the HOPE trial. Hillege et al. (5) found that impaired renal function is a stronger predictor of mortality than impaired cardiac function in advanced chronic heart failure. In addition, microalbuminuria is an independent risk factor for cardiovascular disease (6 -9). Although the mechanism behind the association between compromised renal function and the increased risk for cardiovascular disease remains unknown, it does not appear to involve common risk factors such as hypertension, diabetes, or hyperhomocystinemia (10). Although the effects of renal function impairment on cardiovascular mortality and morbidity have been extensively studied, it is unknown whether the opposite is also true-that is, whether cardiac function affects the outcome of mild renal function loss.The aim of the study presented here was to investigate whether cardiac damage could aggravate a mild state of chronic renal function loss. For this purpose, we used the rat model of unilateral nephrectomy (UnX) as this model shows a very mild state of chronic, mild renal function loss. In this model we introd...

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Section: Surgical Proceduresmentioning

confidence: 99%

Myocardial Infarction Enhances Progressive Renal Damage in an Experimental Model for Cardio-Renal Interaction

Dokkum¹,

Eijkelkamp²,

Kluppel³

et al. 2004

Journal of the American Society of Nephrology

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“…Cell lysates were centrifuged and extracted on Sep-Pak 18 cartridges. Angiotensin peptides were assessed by radioimmunoassay (RIA) after separation on high-performance liquid chromatography (HPLC) (20,22).…”

Section: Angiotensin I and Ii Assaymentioning

confidence: 99%

Role of renin-angiotensin system in activation of macrophages by modified lipoproteins

Rafatian

Milne

Leenen

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Rafatian N, Milne RW, Leenen FH, Whitman SC. Role of reninangiotensin system in activation of macrophages by modified lipoproteins. Am J Physiol Heart Circ Physiol 305: H1309-H1320, 2013. First published August 30, 2013; doi:10.1152/ajpheart.00826.2012.-Angiotensin II favors the development of atherosclerosis. Our goal was to determine if foam cell formation increases angiotensin II generation by the endogenous renin-angiotensin system (RAS) and if endogenously produced angiotensin II promotes lipid accumulation in macrophages. Differentiated THP-1 cells were treated with acetylated low-density lipoproteins (ac-LDL), native LDL (n-LDL), or no LDL. Expression of RAS genes was assessed and angiotensin I/II levels were quantified in media and cell lysate. Ac-LDL increased angiotensin I/II levels and the angiotensin II/I ratio in cells and media after foam cell formation. Renin mRNA or activity did not change, but renin blockade completely inhibited the increase in angiotensin II. Angiotensinogen mRNA but not protein level was increased. Angiotensin-converting enzyme (ACE) and cathepsin G mRNA and activities were enhanced by ac-LDL. Inhibition of renin, ACE, or the angiotensin II receptor 1 (AT 1-receptor) largely abolished cholesteryl ester formation in cells exposed to ac-LDL and decreased scavenger receptor A (SR-A) and acyl-coenzyme A:cholesterol acyltransferase 1 (ACAT-1) protein levels. Inhibition of renin or the AT 1-receptor in cells treated with oxidized LDL also decreased SR-A and ACAT-1 protein and foam cell formation. ac-LDL also increased angiotensin II by human peripheral blood monocyte-derived macrophages, whereas blockade of renin decreased cholesterol ester formation in these macrophages. These findings indicate that, during foam cell formation, angiotensin II generation by the endogenous RAS is stimulated and that endogenously generated angiotensin II is crucial for cholesterol ester accumulation in macrophages exposed to modified LDL. (6,33,34). All components of the renin-angiotensin system (RAS) are present in atherosclerotic lesions (6). ANG II in atherosclerotic lesions localizes in macrophages (28). Human macrophages express all components of the RAS and release ANG II (25). Macrophages also express other enzymes that are able to produce ANG II such as cathepsin G, which can generate ANG II from either angiotensin I (ANG I) or angiotensinogen (29). Low-density lipoprotein (LDL) receptor-deficient atherosclerotic mice with renin deficiency in their bone marrow have reduced atherosclerotic lesion size, suggesting the importance of macrophage-derived ANG II in atherosclerosis (5).Lipid-laden macrophages are the predominant cell type in early stages of atherosclerosis (5) Although the expression of the RAS genes and ANG II release have been shown in macrophages (25), changes in the expression of these genes and their effects on the final product of the system (ANG II) have not yet been studied in foam cells. The role of locally generated ANG II in foam cell formation independently of circulating...

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“…[47][48][49][50] Although its levels in the heart are several times higher than those measured concomitantly in plasma, this does not necessarily imply that Ang II is synthesized in the heart by locally synthesized renin, angiotensinogen, and ACE. First, Ang II present in the heart may have been taken up from the circulation via AT 1 receptor-mediated endocytosis, 51 and second, if local Ang II synthesis has occurred, it may depend on RAS components that are also taken up from the circulation.…”

Section: Ang II Synthesis In the Heart Under Normal Conditionsmentioning

confidence: 99%

“…This approach will lead to an overestimation of the true angiotensin levels or even to the detection of angiotensins in medium that does not contain angiotensins. It should also be kept in mind that in view of the cardiac angiotensin levels measured in vivo, with the use of appropriate prior purification and separation (Ang I, Ϸ5 fmol/g wet wt; Ang II, Ϸ20 fmol/g wet wt), 47,48,49,50 even levels of 5 to 10 fmol/mL are very high, because in most studies, medium was collected from only 1 to 10 million cells, with an estimated wet weight far below 1 g. Sadoshima et al 77 found the Ang II concentration in the medium of serum-deprived cardiomyocytes to increase nearly 100-fold on stretch. This Ang II, which is assumed to be responsible for the hypertrophic 59,77,79,80 or apoptotic 81 response of cardiomyocytes after stretch, appeared to originate from intracellular storage sites, inasmuch as its release was not affected by captopril and not accompanied by Ang I release.…”

Section: Stretch-mediated Ang II Release Frommentioning

confidence: 99%

“…Cardiac Ang II levels increase after a myocardial infarction and in response to pressure and volume overload. 49,71 Most studies investigating the cardiac RAS under pathological conditions have determined changes at the mRNA level. In view of the low to undetectable levels of renin and angiotensinogen mRNA in control hearts, as well as the uncertainties with regard to transcriptional regulation, it is difficult to establish the value of increased mRNA levels in the diseased heart.…”

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Angiotensin II and the Heart

2000

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Abstract-The active end product of the renin-angiotensin system, angiotensin II (Ang II), through the activation of specific Ang II receptors, regulates cardiac contractility, cell coupling, and impulse propagation and is involved in cardiac remodeling, growth, and apoptosis. We review these subjects, as well as the second messengers that are involved, and the synthesis of Ang II in the heart under normal and pathological conditions. Finally, we discuss the possibility that there is an intracrine renin-angiotensin system in the heart that plays a role in the control of cell communication and inward Ca 2ϩ current. (Hypertension. 2000;35:1183-1188.)Key Words: angiotensin Ⅲ heart Ⅲ hypertrophy Ⅲ receptors, angiotensin Ⅲ renin Ⅲ signal transduction A ngiotensin (Ang) II, through the activation of specific Ang II receptors, regulates cardiac contractility, cell communication, and impulse propagation. In addition, Ang II is involved in cardiac remodeling, growth, and apoptosis. In the past 10 years, the concept of a local renin-angiotensin system (RAS) located in the heart and other organs has gradually gained support, particularly with the demonstration that elements of the RAS cascade (ie, renin, angiotensinogen, Ang I, Ang II, and angiotensin-converting enzyme [ACE]) are present in tissues. 1,2 In the present article, we review up-to-date evidence that Ang II receptor activation is related to the different actions of Ang II in the heart. We also discuss renin-and ACE-dependent generation of Ang II at cardiac tissue sites and the evidence that there is an intracrine RAS in the heart. Ang II generation through alternative pathways (eg, through cathepsin D, tonin, or chymase) as well as the cardiac effects of other angiotensin metabolites, eg, Ang III, Ang IV, and Ang-(1-7), and their receptors are outside the scope of this review and will not be discussed. Ang II ReceptorsThe effect of Ang II on cardiac tissue is related to the activation of 2 specific receptors, AT 1 and AT 2 . 3,4 The AT 1 receptor has 2 subtypes: AT 1A and AT 1B . 5 AT 1A receptors are major blood pressure regulators and potent growth stimulators in cardiomyocytes in vivo, whereas AT 1B receptors are involved in the control of vascular tone when AT 1A receptors are absent. 6 Ang II receptors are 7-transmembrane domain receptors whose primary structures have been established by molecular cloning. [7][8][9] The activation of the receptor is coupled to several intracellular proteins, starting with a G protein. 10 The receptor domains that couple to G proteins involve the second and third cytosolic loops and the proximal segment of the carboxy-terminal domain. 10 -12 In the rat, AT 1A , AT 1B , and AT 2 receptors are located on chromosomes 17, 2, and X, respectively. 11 Samyn et al 13 have demonstrated that cardiac AT 1 receptor gene expression is relatively unchanged during fetal and newborn life and that AT 2 receptor mRNA expression is high during fetal development and decreases rapidly after birth. Administration of Ang II to a rat whole embryo c...

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Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors

Cited by 51 publications

References 26 publications

Myocardial Infarction Enhances Progressive Renal Damage in an Experimental Model for Cardio-Renal Interaction

Myocardial Infarction Enhances Progressive Renal Damage in an Experimental Model for Cardio-Renal Interaction

Role of renin-angiotensin system in activation of macrophages by modified lipoproteins

Angiotensin II and the Heart

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