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(Hypertension. 2000;35:1183.)
© 2000 American Heart Association, Inc.

Review Articles

Angiotensin II and the Heart

On the Intracrine Renin-Angiotensin System

Walmor C. De Mello; A. H. Jan Danser

From the Department of Pharmacology (W.C.D.M.), Medical Sciences Campus, University of Puerto Rico, San Juan, and the Department of Pharmacology (A.H.J.D.), Erasmus University Rotterdam, Rotterdam, the Netherlands.

Correspondence to Dr Walmor C. De Mello, Department of Pharmacology, Medical Sciences Campus, PO Box 365067, San Juan, PR 00936-5067.

	Abstract

Top Abstract Introduction Ang II Receptors Ang II Synthesis in... Ang II Synthesis in... Stretch-Mediated Ang II Release... Effect of Ang II... Is an Intracrine RAS... References

 
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 Ca²⁺ current.

Key Words: angiotensin • heart • hypertrophy • receptors, angiotensin • renin • signal transduction

	Introduction

Top Abstract Introduction Ang II Receptors Ang II Synthesis in... Ang II Synthesis in... Stretch-Mediated Ang II Release... Effect of Ang II... Is an Intracrine RAS... References

 
Angiotensin (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 Receptors

Top Abstract Introduction Ang II Receptors Ang II Synthesis in... Ang II Synthesis in... Stretch-Mediated Ang II Release... Effect of Ang II... Is an Intracrine RAS... References

 
The effect of Ang II on cardiac tissue is related to the activation of 2 specific receptors, AT₁ and AT₂.^{3 4} The AT₁ 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 11 12} In the rat, AT_1A, AT_1B, and AT₂ receptors are located on chromosomes 17, 2, and X, respectively.¹¹ Samyn et al¹³ have demonstrated that cardiac AT₁ receptor gene expression is relatively unchanged during fetal and newborn life and that AT₂ receptor mRNA expression is high during fetal development and decreases rapidly after birth. Administration of Ang II to a rat whole embryo culture causes an increase in ventricular growth and myocyte hypertrophy, whereas the AT₁ receptor antagonist losartan and the AT₂ receptor antagonist PD123319, when added together to this preparation, attenuate ventricular development and induce cardiac loop inversions.¹⁴

Exposure of AT_1A and AT_1B receptors to Ang II is followed by translocation of the receptor to intracellular vesicles.¹⁵ Internalization of the Ang II–AT₁ receptor complex occurs with a half-life of <2 minutes.¹⁶ Unlike AT₂ receptors, which are not internalized,¹⁷ AT₁ receptors appear to cycle continuously between endosomal vesicles and the plasma cell membrane.¹⁸ In agreement with this contention, AT₁ receptors in rat myocytes have been localized in the sarcolemma, T tubules, and nuclei.¹⁹ Internalized Ang II is either degraded in the cell or exerts intracellular effects. In support of the latter, evidence is available that Ang II couples to a nuclear binding site²⁰ and that binding of Ang II to a chromatin high-affinity receptor leads to a conformational change in chromatin.²¹ Recently, a soluble high-affinity binding protein for Ang II was localized in the cytosol of neonatal rat cardiac cells with a mass of 78 kDa.²² Intracellular dialysis of Ang II in adult rat myocytes reduces cell communication, an effect abolished by intracellular administration of losartan.²³ Similarly, the intracellular actions of Ang II in vascular smooth muscle cells are suppressed by the AT₁ receptor antagonist candesartan.²⁴ These findings indicate that there may be a functional intracellular Ang II receptor similar to the AT₁ receptor, although further studies are necessary to clarify this point.

The signaling mechanism of Ang II receptors is quite well defined. Activation of AT₁ receptors results in the initiation of a variety of events, such as the stimulation of phospholipase C, with subsequent activation of protein kinase C (PKC) and release of Ca²⁺ from intracellular depots. In addition, tyrosine kinase and mitogen-activated protein kinase are phosphorylated.²⁵ Interestingly, AT₂ receptor blockade increments the early signals of AT₁ receptor–mediated cardiac growth responses in the hypertrophied rat heart,^{26 27} suggesting that AT₂ receptors counteract the effects of AT₁ receptors. The establishment of left ventricular hypertrophy in spontaneously hypertensive rats is associated with increased expression of AT_1A and AT_1B receptors.²⁸ AT₂ receptors are upregulated by interleukin-1ß and insulin, whereas an increase in intracellular Ca²⁺-activated PKC as well as in several growth factors (epidermal growth factor, nerve growth factor, and platelet-derived growth factor) induces a downregulation of AT₂ receptors.²⁹ AT₂ receptors activate the kinin/NO/cGMP system and stimulate protein tyrosine phosphatase and serine/threonine phosphatase.²⁹ Protein tyrosine phosphatase stimulation inactivates AT₁ receptor–activated mitogen-activated protein kinase,³⁰ and this may explain the above interaction between AT₁ and AT₂ receptors. In addition, activation of extracellular signal–regulated kinase, which underlies the mitogenic or hypertrophic response after AT₁ receptor stimulation, can be reversed by AT₂ receptor–mediated stimulation of serine/threonine phosphatase 2A.³¹

Interaction between AT₁ and AT₂ receptors represents a topic of interest, particularly to heart pathology. In pigs, for instance, reduction in infarct size induced by AT₁ receptor blockade occurs through a signal cascade involving AT₂ receptor activation, bradykinin, and prostaglandins.³² In infarcted rats, the beneficial effects of AT₁ receptor antagonists on left ventricular end-diastolic and end-systolic volumes, ejection fraction, interstitial fibrosis, and myocyte hypertrophy are suppressed by simultaneous intravenous administration of an AT₂ receptor antagonist.^{33 34} Similarly, AT₂ receptors in the failing hearts of cardiomyopathic hamsters counteract the AT₁ receptor–induced progression of interstitial fibrosis.³⁵ In this regard, it is of interest that the density of AT₂ receptors in the perivascular, endocardial, and infarcted areas of hearts of patients with dilated cardiomyopathy or severe ischemic heart disease is greatly increased, particularly in areas of collagen deposition or fibrosis.³⁶ Moreover, >80% of the Ang II receptors in right atrial biopsies obtained from patients with coronary disease is of the AT₂ type, and these receptors are mainly associated with fibrous tissue.³⁷

Recently, it was found that Ang II induces apoptosis in cultured neonatal rat ventricular myocytes through the activation of AT₁ receptors and PKC.³⁸ Because p53 increased the expression of angiotensinogen in these cells, it was postulated that p53 induces apoptosis through the stimulation of Ang II release from myocytes and subsequent AT₁ receptor activation.³⁸ However, apoptosis has also been attributed to AT₂ receptor stimulation and its second messenger ceramide.^{39 40}

Studies in transgenic animals have shed further light on the importance of AT_1A and AT₂ receptors in cardiac function, growth, and remodeling.^{41 42 43 44} AT_1A receptor knockout mice display less left ventricular remodeling and greater survival after myocardial infarction.⁴³ Disruption of the mouse AT₂ receptor gene resulted in a significant increase in blood pressure,⁴² whereas cardiac-specific overexpression of AT₂ receptors in mice attenuated the AT₁ receptor–mediated pressor and chronotropic effects.⁴⁴ Furthermore, in humans, the AT₁ receptor A/C¹¹⁶⁶ polymorphism and the A/G¹⁶⁷⁵ gene variant of the AT₂ receptor modulate left ventricular hypertrophy.^{45 46}

In summary, activation of cell-surface AT₁ receptors is responsible for most of the Ang II–mediated effects in the heart, specifically those on growth and remodeling, and some of these effects are counteracted by AT₂ receptor activation. In addition, Ang II may exert effects through binding to intracellular AT₁ receptor–like proteins.

	Ang II Synthesis in the Heart Under Normal Conditions

Top Abstract Introduction Ang II Receptors Ang II Synthesis in... Ang II Synthesis in... Stretch-Mediated Ang II Release... Effect of Ang II... Is an Intracrine RAS... References

 
Ang II has been demonstrated in cardiac tissue by many authors.^{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 AT₁ 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. To quantify angiotensin uptake from plasma, the tissue and plasma levels of endogenous and radiolabeled Ang I and Ang II were measured during infusions of ¹²⁵I-labeled Ang I and Ang II.⁵⁰ The results indicated that at steady state, the cardiac concentrations of ¹²⁵I-Ang I are <5% of its levels in plasma, whereas the concentrations of cardiac ¹²⁵I-Ang II are 90% of plasma ¹²⁵I-Ang II. At the same time, the cardiac tissue concentration of endogenous Ang I was similar to the plasma concentration of endogenous Ang I, whereas the tissue concentration of endogenous Ang II was 4 to 5 times higher than the plasma concentration of endogenous Ang II. From these data, it can be calculated that >90% of cardiac tissue Ang I is synthesized at tissue sites and is not derived from the circulation. Furthermore, >75% of cardiac tissue Ang II is also synthesized at tissue sites, and its source is in situ–synthesized Ang I rather than plasma Ang I. Thus, these findings clearly support the concept of angiotensin synthesis at cardiac tissue sites.

Renin mRNA levels in normal hearts are low or undetectable,^{52 53 54} and the cardiac levels of renin, Ang I, and Ang II decrease in parallel with the plasma levels of these RAS components to levels close to or below the detection limit after a bilateral nephrectomy.^{47 55} Furthermore, renin and angiotensins cannot be demonstrated in the perfusate of the isolated Langendorff-perfused rat heart^{56 57} or in the supernatant of serum-deprived neonatal rat cardiomyocytes.^{58 59} Therefore, it appears that the renin responsible for cardiac angiotensin generation is renin of renal origin that reaches the heart via the circulation. Renin may enter the heart either through diffusion in the interstitial space^{56 60} or through binding to renin receptors.^{61 62 63 64} The source of angiotensinogen in the heart is currently unknown. Although angiotensinogen mRNA can be demonstrated in the heart, its cardiac levels are <0.1% of the angiotensinogen mRNA levels in the liver.^{53 65 66} Moreover, the isolated Langendorff-perfused 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. The angiotensinogen concentrations present in cardiac tissue are compatible with the idea that angiotensinogen diffuses freely from the blood compartment into the interstitial space.^{47 60} Studies in a modified version of the rat Langendorff-perfused heart, allowing the separate collection of coronary effluent and interstitial transudate, showed that angiotensinogen, when added to the perfusion buffer, rapidly entered the interstitial space.⁵⁶ At steady state, its levels in interstitial fluid and coronary effluent were comparable. Evidence for binding of angiotensinogen to cardiac membranes could not be obtained.⁴⁷

Local synthesis of ACE at cardiac tissue sites does occur beyond doubt. ACE mRNA is readily detectable in the heart,^{67 68} and ACE has been demonstrated in the heart by autoradiography,⁶⁹ as well as by measurement of its activity in cardiac homogenates.⁶⁸ Moreover, Ang I is converted to Ang II in the isolated perfused rat heart.⁵⁷ Normally, the presence of ACE in the heart is limited to the coronary vascular endothelial cells and the endocardium.⁷⁰ In summary, Ang II synthesis occurs at cardiac tissue sites and depends on renin and angiotensinogen taken up from the circulation.

	Ang II Synthesis in the Heart Under Pathological Conditions

Top Abstract Introduction Ang II Receptors Ang II Synthesis in... Ang II Synthesis in... Stretch-Mediated Ang II Release... Effect of Ang II... Is an Intracrine RAS... References

 
Despite the lack of renin and angiotensinogen synthesis at cardiac tissue sites under normal conditions, it is not unlikely that the renin and angiotensinogen genes at these sites are switched on in response to pathological conditions. 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. Pieruzzi et al⁷² have described increases in renin mRNA in the rat heart in response to volume overload, whereas Iwai et al⁶⁶ were unable to confirm these findings. No change in cardiac angiotensinogen mRNA was found in the volume-overload model.^{54 66} In contrast, Lindpaintner et al⁶⁵ reported a transient activation of angiotensinogen mRNA in the noninfarcted left ventricle of rats after a coronary artery ligation. Part of these discrepancies might be related to the inflammatory response that will occur after myocardial infarction but not after the induction of volume overload. Ang II, through its effect on prostaglandin synthesis,⁷³ will affect this response.

Detailed information on myocardial renin-angiotensinogen dynamics during pressure overload–induced cardiac hypertrophy and after myocardial infarction has been obtained by Heller et al⁶⁰ and Hirsch et al.⁷⁴ They found cardiac renin to vary directly with plasma renin under all circumstances. Similarly, the rise in cardiac renin occurring in subjects with end-stage heart failure was accompanied by a parallel increase in plasma renin.⁶² Thus, on the basis of renin protein measurements in cardiac tissue, no evidence was obtained for significant cardiac renin production under pathological conditions. It is not known whether the uptake of circulating renin is altered in infarcted or hypertrophying areas of the diseased heart. Demonstration of significant angiotensinogen production in the heart under pathological conditions is even more difficult, because increased consumption by renin may mask local production. Indeed, decreased rather than increased angiotensinogen levels were found in failing human hearts,⁶² whereas in infarcted rat hearts or in rat hearts that had been exposed to pressure overload, no changes in angiotensinogen content were observed.^{60 74} Finally, with regard to ACE, the findings on changes in mRNA levels in diseased hearts are in full agreement with the findings on changes in its protein levels under these conditions. Cardiac tissue ACE increases after myocardial infarction as well as during pressure and volume overload–induced left ventricular hypertrophy.^{67 68 69 72} Under these conditions, the localization of ACE may no longer be limited to the endothelium. In humans, after myocardial infarction, ACE can be detected in the remaining viable cardiomyocytes near the infarct scar of the aneurysmal left ventricle as well as in fibroblasts, vascular smooth muscle cells, and macrophages in the scar area itself.⁷⁵ In rats, after coronary occlusion, ACE was demonstrated in fibroblasts in the healthy hypertrophying part of the heart.⁷⁶ Taken together, cardiac Ang II levels increase under pathological conditions because (1) the elevated renin levels in blood plasma under these circumstances allow the heart to sequester more renin from the circulation, and (2) the cardiac ACE levels are increased. The rise in cardiac Ang II generation may result in decreased cardiac angiotensinogen levels.

	Stretch-Mediated Ang II Release From Myocytes: Is Ang II Synthesized Intracellularly?

Top Abstract Introduction Ang II Receptors Ang II Synthesis in... Ang II Synthesis in... Stretch-Mediated Ang II Release... Effect of Ang II... Is an Intracrine RAS... References

 
According to several studies, serum-deprived cardiomyocytes release angiotensins into the culture medium.^{77 78 79} This is remarkable, in view of the fact that cardiomyocytes do not synthesize renin or angiotensinogen in measurable quantities.⁵⁹ One possibility is that the cells have sequestered renin and/or angiotensinogen from the serum-containing medium that is normally used to culture the cells.⁶³ The Ang I and II levels in the medium showed huge variations, from <10 to >1000 fmol/mL. Part of these discrepancies may be due to the fact that angiotensins were sometimes measured by direct radioimmunoassays (ie, without prior purification and/or separation from material cross-reacting with the Ang I and II antibodies applied in these assays). 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, 5 fmol/g wet wt; Ang II, 20 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 al⁷⁷ 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 apoptotic⁸¹ 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.⁷⁷ Immunoelectron microscopy confirmed the existence of secretory granule-like structures containing Ang II in ventricular cardiomyocytes.⁷⁷ Dostal et al⁷⁸ did not observe these granule-like structures and localized intracellular Ang II in the perinuclear region of neonatal rat cardiomyocytes and fibroblasts. Stretch is assumed to cause an upregulation of RAS components in cardiomyocytes,^{80 81} and this would explain why the Ang II levels in the medium are also elevated 20 to 24 hours after the initiation of stretch.⁸¹ However, the reports on elevated renin and ACE mRNA levels were not supported by protein measurements,^{77 79} suggesting that increases in expression may not be translated to the protein level. In addition, not all authors were able to observe a rise in Ang II after stretch.^{58 59} Taken together, therefore, the initial report by Sadoshima et al on Ang II release after stretch has not been unequivocally confirmed by others. It is possible that differences in experimental conditions have played a role. Furthermore, the Ang II in intracellular storage sites may have been derived, via AT₁ receptor–mediated endocytosis,⁵¹ from the serum-containing medium used to culture the cells before stretch.

	Effect of Ang II on Heart Cell-to-Cell Coupling

Top Abstract Introduction Ang II Receptors Ang II Synthesis in... Ang II Synthesis in... Stretch-Mediated Ang II Release... Effect of Ang II... Is an Intracrine RAS... References

 
Ang II regulates intercellular communication in cardiac muscle.⁸² For instance, in hearts of normal adult rats and cardiomyopathic hamsters, at a late stage of the disease, Ang II administered to the extracellular fluid reduces gap junction conductance within seconds.^{83 84} This effect, which was blocked by losartan, is dependent on activation of PKC because it was abolished by staurosporine.^{84 85} In the failing hamster heart, enalapril increased junctional conductance by 219±20%.⁸⁴ Although the mechanism of action of enalapril on cell coupling is not known, its effect on junctional conductance may be responsible, at least in part, for the increment in conduction velocity that is normally seen with ACE inhibitors in cardiac muscle of the failing heart.⁸⁵ Furthermore, this effect might play a role in the prevention of slow conduction and reentry, 2 major factors involved in the generation of cardiac arrhythmias.⁸⁶

	Is an Intracrine RAS Involved in the Regulation of Heart Function?

Top Abstract Introduction Ang II Receptors Ang II Synthesis in... Ang II Synthesis in... Stretch-Mediated Ang II Release... Effect of Ang II... Is an Intracrine RAS... References

 
We investigated the role of an intracrine RAS in the regulation of intercellular communication by using ventricular myocytes from rats and hamsters.^{23 84 87 88} Renin or Ang I dialyzed into cell pairs of adult rats caused a decrease in junctional conductance,²³ and the effect of renin was appreciably increased by simultaneous administration of angiotensinogen.⁸⁷ The effect of intracellular Ang I on cell coupling is related to its conversion to Ang II, because enalaprilat administered to the cytosol reduced the effect of Ang I. Moreover, Ang II, when administered to the cytosol, reduced the junctional conductance by 60% within 45 seconds.²³ The latter effect was suppressed by intracellular administration of losartan, suggesting that it is related to the activation of a receptor similar to the AT₁ receptor.²³ In myocytes from cardiomyopathic hamsters, intracellular dialysis of Ang I also caused suppression of cell communication, and this effect was again drastically reduced by intracellularly added enalaprilat.⁸⁴ In myocytes from adult rats, in which Ang II has a negative inotropic action, intracellular administration of Ang II reduced the inward Ca²⁺ current, whereas in myocytes from adult hamsters, in which Ang II exerts a positive inotropic effect, the opposite was found.⁸⁸ In this respect, it is of interest to note that in nondifferentiated hybrid NG108-15 cells (neuroblastomaxglioma), Ang II, through AT₂ receptor stimulation and activation of protein tyrosine phosphatase, decreases T-type Ca²⁺ current,⁸⁹ whereas in adrenal glomerulosa cells, Ang II, through AT₁ receptor stimulation and activation of a G_i protein, increases T-type Ca²⁺ channel current.⁹⁰ Finally, Ang II causes rapid alkalinization in cultured neonatal rat ventricular myocytes. This effect did not involve the Na⁺-H⁺ exchanger and could be blocked by PD123319, suggesting that it is AT₂ receptor–mediated.⁹¹ Alkalinization might be related to the effects of Ang II on cardiac contractility but does not explain the decline in cell communication induced by Ang II in myocytes, because alkalinization increases cell coupling (see Reference ⁸² ).

In summary, Ang II, when added extracellularly, reduces cell coupling and conduction velocity in cardiac muscle. ACE inhibitors exert opposite effects. When administered intracellularly into cardiac myocytes, Ang II also reduces cell coupling and controls inward Ca²⁺ current, possibly through stimulation of an intracellular AT₁ receptor. Intracellular Ang II may be derived from the extracellular space, through AT₁ receptor–mediated endocytosis.⁵¹ Alternatively, Ang II may have been synthesized intracellularly,⁵⁷ for instance, by plasma-derived renin that, after its diffusion into the interstitial space,^{56 60 74} has been internalized by myocytes.⁶³ Taken together, these findings support the existence of an intracrine RAS that is involved in the regulation of heart contractility and impulse propagation.

	Acknowledgments

 
This work was supported by grants from the American Heart Association (Dr De Mello), the National Institutes of Health (HL-34148, HL-532943, and RR-03051) (Dr De Mello), and the Netherlands Heart Foundation (NHS 97.186) (Dr Danser).

Received November 22, 1999; first decision December 22, 1999; accepted April 7, 2000.

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