Selective Activation of Cardiac Angiotensinogen Gene Expression in Post-infarction Ventricular Remodeling in the Rat

Lindpaintner, Klaus; Lü, Wenyan; Niedermajer, Nikolaj; Schieffer, Bernhard; Just, H; Ganten, Detlev; Drexler, Helmut

doi:10.1006/jmcc.1993.1017

Cited by 186 publications

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“…These changes enhance local Ang II production, which is the likely stimulus for hypertrophy in noninfarcted myocardium. 18 In addition to the activation of the RAS and adrenergic receptors locally, small mechanical strains induced by elevated wall stresses sensed by infarcted and noninfarcted myocardium have been implicated in hypertrophy. 12 Small mechanical stretches of myocytes demonstrate a tight bidirectional relationship between wall stress and myocyte hypertrophy, 8 which resembles that between stress and hypertrophy in the intact heart.…”

Section: Remodeling and Hypertrophymentioning

confidence: 99%

“…Although coronary hemodynamic data have suggested a balanced effect of ACE inhibitors on the coronary circulation, one study in patients with heart failure and angina indicated that such treatment may worsen ischemia, because of the hypotension that compromises myocardial perfusion. 48 Importantly, ACE inhibition may have a direct effect on myocardial tissue, 4,8,18 preventing the inappropriate growth and hypertrophy stimulated by Ang II and other growth factors.…”

Section: Ace Inhibitionmentioning

confidence: 99%

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Left Ventricular Remodeling After Myocardial Infarction

2000

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L eft ventricular remodeling is the process by which ventricular size, shape, and function are regulated by mechanical, neurohormonal, and genetic factors. 1,2 Remodeling may be physiological and adaptive during normal growth or pathological due to myocardial infarction, cardiomyopathy, hypertension, or valvular heart disease ( Figure 1). This article will review postinfarction remodeling, pathophysiological mechanisms, and therapeutic intervention. Pathophysiology Postinfarction Left Ventricular RemodelingThe acute loss of myocardium results in an abrupt increase in loading conditions that induces a unique pattern of remodeling involving the infarcted border zone and remote noninfarcted myocardium. Myocyte necrosis and the resultant increase in load trigger a cascade of biochemical intracellular signaling processes that initiates and subsequently modulates reparative changes, which include dilatation, hypertrophy, and the formation of a discrete collagen scar. Ventricular remodeling may continue for weeks or months until the distending forces are counterbalanced by the tensile strength of the collagen scar. This balance is determined by the size, location, and transmurality of the infarct, the extent of myocardial stunning, the patency of the infarct-related artery, and local tropic factors. 1,3 The myocardium consists of 3 integrated components: myocytes, extracellular matrix, and the capillary microcirculation that services the contractile unit assembly. Consideration of all 3 components provides important insights into the remodeling process and a rationale for future therapeutic strategies. The cardiomyocyte is terminally differentiated and develops tension by shortening. The extracellular matrix provides a stress-tolerant, viscoelastic scaffold consisting of type I and type III collagen that couples myocytes and maintains the spatial relations between the myofilaments and their capillary microcirculation. 4,5 The collagen framework couples adjacent myocytes by intercellular struts that align myofilaments to optimize force development, distribute force evenly to the ventricular walls, and prevent sarcomeric deformation. 5 Myocardial infarction results in the migration of macrophages, monocytes, and neutrophils into the infarct zone; this initiates intracellular signaling and neurohormonal activation, which localizes the inflammatory response. Changes in circulatory hemodynamics are determined primarily by the magnitude of myocyte loss, the stimulation of the sympathetic nervous system and renin-angiotensin-aldosterone system, and the release of natriuretic peptides.Postinfarction remodeling has been arbitrarily divided into an early phase (within 72 hours) and a late phase (beyond 72 hours). The early phase involves expansion of the infarct zone, 5 which may result in early ventricular rupture or aneurysm formation. Late remodeling involves the left ventricle globally and is associated with time-dependent dilatation, the distortion of ventricular shape, and mural hypertrophy. The failure to normalize increa...

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Section: Remodeling and Hypertrophymentioning

confidence: 99%

Section: Ace Inhibitionmentioning

confidence: 99%

Left Ventricular Remodeling After Myocardial Infarction

2000

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“…3 Renin mRNA may be present in the heart in low concentrations, [4][5][6][7] but observations on the effect of bilateral nephrectomy in pigs demonstrated that most, if not all, renin in the heart is derived from the kidney, at least under normal conditions. 3 Angiotensinogen gene expression is also low in the normal heart, 7,8 and experiments using the isolated perfused rat heart seem to indicate that the heart produces little Ang I and II when angiotensinogen is not added to the perfusion fluid. 9 In contrast, the synthesis of ACE in the normal heart is an established fact.…”

mentioning

confidence: 99%

“…10 -13 Angiotensinogen and ACE gene expression may be upregulated under pathological conditions. 8,11,13 The study reported here focuses on the normal heart and is carried out in pigs. It addresses the following questions: (1) How much of the Ang I and II in cardiac tissue is derived from the circulation?…”

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confidence: 99%

Angiotensin Production by the Heart

et al. 1998

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Background —Beneficial effects of ACE inhibitors on the heart may be mediated by decreased cardiac angiotensin II (Ang II) production. Methods and Results —To determine whether cardiac Ang I and Ang II are produced in situ or derived from the circulation, we infused 125 I-labeled Ang I or II into pigs (25 to 30 kg) and measured 125 I-Ang I and II as well as endogenous Ang I and II in cardiac tissue and blood plasma. In untreated pigs, the tissue Ang II concentration (per gram wet weight) in different parts of the heart was 5 times the concentration (per milliliter) in plasma, and the tissue Ang I concentration was 75% of the plasma Ang I concentration. Tissue 125 I-Ang II during 125 I-Ang II infusion was 75% of 125 I-Ang II in arterial plasma, whereas tissue 125 I-Ang I during 125 I-Ang I infusion was <4% of 125 I-Ang I in arterial plasma. After treatment with the ACE inhibitor captopril (25 mg twice daily), Ang II fell in plasma but not in tissue, and Ang I and renin rose both in plasma and tissue, whereas angiotensinogen did not change in plasma and fell in tissue. Tissue 125 I-Ang II derived by conversion from arterially delivered 125 I-Ang I fell from 23% to <2% of 125 I-Ang I in arterial plasma. Conclusions —Most of the cardiac Ang II appears to be produced at tissue sites by conversion of in situ–synthesized rather than blood-derived Ang I. Our study also indicates that under certain experimental conditions, the heart can maintain its Ang II production, whereas the production of circulating Ang II is effectively suppressed.

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“…Although angiotensinogen mRNA can be demonstrated in the heart, its cardiac levels are Ͻ0.1% of the angiotensinogen mRNA levels in the liver. 53,65,66 Moreover, the isolated Langendorffperfused rat heart does not release angiotensinogen, 56 nor could angiotensinogen be demonstrated in the supernatant of serum-deprived neonatal rat cardiomyocytes and fibroblasts. 59 Thus, evidence for the production of angiotensinogen at cardiac tissue sites is not available, and most likely, the majority of angiotensinogen in the heart is also derived from the circulation.…”

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confidence: 99%

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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Selective Activation of Cardiac Angiotensinogen Gene Expression in Post-infarction Ventricular Remodeling in the Rat

Cited by 186 publications

References 0 publications

Left Ventricular Remodeling After Myocardial Infarction

Left Ventricular Remodeling After Myocardial Infarction

Angiotensin Production by the Heart

Angiotensin II and the Heart

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