Molecular Signaling Mechanisms of the Renin-Angiotensin System in Heart Failure

A Perspective on the Renin Angiotensin Aldosterone System

Although Bright (1827) first associated kidney hardness with a strong arterial pulse, current knowledge regarding the role of the renin angiotensin aldosterone system to homeostasis has been gained over the last 50 years. It is not to be denied that the discoveries associated with characterization of this critically important circulating and tissue-borne hormonal system transcended the field of cardiovascular medicine, having a major impact on the research and treatment of renal, neurological, hepatic, and skeletal diseases. The broad role of the hormone angiotensin II (Ang II) and its biologically related main peptides—angiotensin-(1-7) (Ang-[1-7]), angiotensin III (Ang III), and angiotensin-(1-9) (Ang-[1-9])—in modulating immune and inflammation responses is a reason why drugs acting to inhibit, or block renin-angiotensin system effectors are showing benefits above and beyond their original indication. Antitumoral actions are documented for drugs preventing Ang II actions or increasing Ang-(1-7) activity. The ubiquitous mechanisms accounting for such a diverse spectrum of actions involve multifactorial signaling pathways.

This chapter reviews the molecular mechanisms of the renin-angiotensin system, and underscores a major opportunity to develop a new generation of drugs with an increased capacity to reach the intracellular sites at which locally borne angiotensins modulate organ function. The clinical applications of antagonizing the renin-angiotensin system are reviewed in Chapter 37 . For the convenience of the reviewer, a summary of the abbreviations used is presented at the end of this chapter.

The Biochemical Physiology of the Renin Angiotensin System

Initial studies of Ang II formation and action were influenced by the prevailing assumption that this peptide acted as a circulating hormone originating from the action of renal renin on the angiotensinogen (AGT) released from the liver. During the decades preceding the current millennium, enzymological studies were driven to answer how renal renin acted on the rate limiting step protein substrate that accounted for the generation of angiotensin peptides. Over a span of probably two decades, the accepted view of the system was that renal renin generated angiotensin I (Ang I) by splitting the bond between leucine ¹⁰ (Leu ¹⁰ ) and leucine ¹¹ (Leu ¹¹ ) from the liver derived AGT substrate. The early conclusions were partly misleading, as they failed to realize that valine ¹¹ (Val ¹¹ ) is substituted for Leu ¹¹ in the human AGT molecule. Circulating Ang I was then further processed into Ang II by the action of angiotensin-converting enzyme (ACE), which hydrolyzed the bond between phenylalanine ⁸ (Phe ⁸ ) and histidine ⁹ (His ⁹ ) in the C-terminus of the Ang I molecule. The resulting molecule was Ang II, the main bioactive peptide of the renin angiotensin system. This conceptual understanding of the biochemical pathways for Ang II production implies the existence of a linear system in which the hydrolytic activity of renin and ACE sequentially cleaved Ang I from AGT and Ang II from Ang I. The 1980s began to force a reconsideration of these concepts as identification of Ang-(1-7) in Ferrario’s research program, and the heptapeptide fragment angiotensin IV (Ang IV) challenged the prevailing simplistic understanding of Ang II singularity in the regulation of blood pressure and fluid balances ( Fig. 5.1 ). A diagram of the family of angiotensin peptides derived from the N-terminal end of AGT is documented in Table 5.1 . Table 5.2 illustrates the location of the extended number of humans’ genes now recognized to account for the expression and function of the renin angiotensin system.

Fig. 5.1, Counterbalancing arms of the renin-angiotensin system.

TABLE 5.1

The Family of Recognized Biologically Active Angiotensins Sequences in Humans

Peptide	Amino Acid Sequence
Angiotensinogen (AGT)	H ₂ N-Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ -His ⁹ -Leu ¹⁰ -Val ¹¹ -Ile ¹² -His ¹³ -Asn ¹⁴ -Glu ¹⁵ -COOH
Angiotensin–(1-12)	H ₂ N-Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ -His ⁹ -Leu ¹⁰ -Val ¹¹ -Ile ¹² -COOH
Angiotensin–(1-10) (Ang I)	H ₂ N-Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ -His ⁹ -Leu ¹⁰ -COOH
Angiotensin–(1-9)	H ₂ N-Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ -His ⁹ -COOH
Angiotensin–(1-8) (Ang II)	H ₂ N-Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ -COOH
Angiotensin A	H ₂ N-Ala ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -Phe-COOH ⁸
Angiotensin–(1-7) [Ang-(1-7)]	H ₂ N-Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -COOH
Almandine	H ₂ N-Ala ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -COOH
Angiotensin–(1-5)	H ₂ N-Asp ¹ -Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -COOH
Angiotensin-(2-8) (Ang III)	H ₂ N- Arg ² -Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ -COOH
Angiotensin–(3-8) (Ang IV)	H ₂ N- Val ³ -Tyr ⁴ -Ile ⁵ -His ⁶ -Pro ⁷ -Phe ⁸ -COOH

Valine in position 11 (Val ¹¹ ) is present in the human angiotensinogen sequence while Leucine is the amino acid contained in rodents.

TABLE 5.2

Location of Primary Genes Accounting for RAS Functions

Data reported for genes expressed in Homo sapiens (human) as compiled by the National Center for Biotechnology Information ( https://www.ncbi.nlm.nih.gov/ ).

Gene	Chromosomal Location
Angiotensin-converting enzyme (ACE)	long (q) arm of chromosome 17 at position 23.3
Angiotensin-converting enzyme 2 (ACE2)	long (q) arm of chromosome X at position 22.2
Angiotensin II type 1 receptor (AGTR1)	long (q) arm of chromosome 3 at position 24
Angiotensin II type 2 receptor (AGTR2)	long (q) arm of chromosome X at position 23
Angiotensinogen (AGT)	long (q) arm of chromosome 1 at position 42.2
Carboxypeptidase A1	long (q) arm of chromosome 7 at position 32.2
Chymase (CMA1)	long (q) arm of chromosome 14 at position 12
Elastase-2 (ELA2)	short arm (p) of chromosome 19 at position 13.3
Mas receptor (MAS1)	long (q) arm of chromosome 6 at position 25.3
MrgD Receptor	long (q) arm of chromosome 11 at position 13.3
Renin (REN)	long (q) arm of chromosome 1 at position 32.1

As illustrated in Table 5.1 , humans and rodents differ in the molecular sequence of the amino terminal end of the AGT molecule as valine replaces leucine in position 11. Additional significant differences exist in the amino acid sequence of human AGT beyond valine ¹¹ (Val ¹¹ ). Table 5.1 shows that the human amino acid chain beyond Val ¹¹ is composed of Ile ¹² -His ¹³ -Asn ¹⁴ -Glu ¹ , while in the rat the amino acid sequence contains Tyr ¹² -Tyr ¹³ -Ser ¹⁴ -Lys ¹⁵ . These amino acid differences influence the identity and affinity of the enzymes cleaving the biologically active angiotensins from AGT. Indeed, it has been well documented that rat renin has no hydrolytic activity on human AGT.

Contemporary research affirms the view that the renin angiotensin system is a complex system in which biological diversity is revealed not only by the different effects of the products generated from either Ang I or Ang II but also through its receptors and peptide-forming and degrading enzymes. That the renin angiotensin system was far more complex than generally accepted, and that this complexity guarantees a well-tuned adaptation of the blood supply of the body compartments to all physiological conditions, was advanced as early as 1991.

The principles of network biology allow a more precise understanding of the complex interactions between enzymes and products within the renin angiotensin system. The behavior of protein-protein and molecular interactions of the renin angiotensin system network is determined by the orchestrated activity of several components interacting with each other through pair-wise interactions. Our studies suggest the existence within the renin angiotensin system of four primary nodes for the deterministic control of hormone (Ang II and Ang-[1-7]) expression signaling cellular functions in terms of growth, contractility, protein synthesis, and gene expression. Fig. 5.2 shows the nodes at which enzymes catalyze reactions transforming one metabolite into another. The four nodes are represented as (a) Aogen processing enzymes; (b) neutral endopeptidases (NEPs; see also Chapter 9 ); (c) ACE; and (d) ACE2. At each node, a regulated process determines the secondary processing of a protein/peptide to a corresponding shorter fragment destined to serve as either a substrate for an additional processing at a secondary node or a final signaling action on the cell’s receptor. At the first node (Aogen processing enzymes), AGT, the sole known identified substrate for the generation of angiotensin peptides, is catalyzed into forming Ang I directly via circulating or tissue expressed renin. Within this same node, however, our recent studies show that AGT is a substrate generating another Ang I-forming precursor, the dodecapeptide angiotensin-(1-12) (Ang-[1-12]), by an enzyme that is not renin. The intermediate products upstream from Ang I (Ang I or Ang-[1-12]) now become substrates to be acted upon by either the neprilysin (NEPs node; see also Chapter 9 ) or the ACE node where these enzymes cleave Ang I to generate Ang II (ACE node) or transform Ang I into Ang-(1-7) (NEPs node). Importantly, the ACE node also functions to regulate the concentration of Ang-(1-7), since ACE degrades this heptapeptide into Ang-(1-5) (not shown). The fourth node (ACE2) cleaves Ang II into Ang-(1-7).

Fig. 5.2, A detailed summary of the biotransformation pathways generating biologically active angiotensins comprises enzymes from distinct endopeptidase and carboxypeptidase families. ACE, Angiotensin-converting enzyme; ACE2, angiotensin-converting enzyme 2; APA , aminopeptidase A; CPA1 and CPA2 , carboxypeptidase A1 and A2; PCP , prolyl-carboxypeptidase; PEP, prolyl endopeptidase.

Establishing the characteristics of the factors regulating the activity of each node is not a trivial matter, as each component of the system can exert a regulatory influence on either the enzymes’ expression or activity and the product generated at each node. For example, Ang II plasma or tissue concentrations shows a feed forward interaction with the Ang I-forming enzyme node as the peptide stimulates the expression of AGT transcripts in the liver, heart, and kidneys. Interestingly, Ang-(1-7) modulates the activity of the ACE node by acting as a weak endogenous inhibitor of the C-terminal domain of the enzyme. In addition, Ang II exerts a negative regulatory interaction on ACE2 gene expression, a feedback interaction that is neutralized by Ang-(1-7).

Renin and Pro-Renin

The enzyme renin can be ubiquitously expressed by a variety of cells, as new evidence suggests its critical evolutionary involvement in tissue homeostasis only in part through its role in regulating body fluid volumes. Although renin is found in many different tissues, its highest expression in the juxtaglomerular cells of renal afferent arterioles constitutes the pivotal sensory mechanism that determines its release into the circulation. Importantly, other renal locations for renin synthesis and release are found in a subset of mesangial cells, arteriolar smooth muscle cells, interstitial pericytes, and distal nephrons and renal collecting duct. Studies reporting the existence of renin and prorenin in distal nephrons and collecting ducts substantiate the potential for renal tubular Ang II formation as an alternative mechanism that, independent of the blood pressure and sodium sensory mechanisms of the juxtaglomerular apparatus and the macula densa, could contribute to the pathogenesis of essential hypertension. ^. The active renin enzyme synthesized as preprorenin is converted into the active releasable form through loss of the signal peptide and removal of the 43-amino-acid pro-segment contained in prorenin. The discovery of a prorenin receptor (PPR) revealed a nonproteolytic mechanism for the activation of renin through the exposure of its catalytic site. Deletion of 10 bp in exon 5 of the Ren gene in the rat caused inactivation of the renin gene, loss of renin granules in juxtaglomerular cells, and significant alterations in renal morphology comparable to those obtained with renin cells ablation in mice.

It has not been possible to find sufficient discriminative renin activity by assay procedures in the circulation as a superior biomarker of an overactive renin angiotensin system. This failure contributed to the search for renin expression and action within the tissue environment, particularly within the vascular wall and the heart. It was assumed that renin present in the extracellular milieu of the heart and blood vessels could generate Ang I from the plasma substrate, leading to Ang II formation by the action of ACE contained by vascular endothelial cells or perivascular tissue. No definitive conclusion has been reached as to whether renin is synthesized by cells in tissues other than the kidneys or its presence in nonrenal tissues reflects a cellular uptake mechanism.

Renin release from juxtaglomerular cells is modulated by the renal baroreceptor through changes in renal perfusion pressure, the sensory of sodium (Na ⁺ ) by the macula densa, and renal sympathetic nerve activity. Additional regulation of active renin secretion is exerted by Ang II through renal AT ₁ receptors, the primary intracellular second messenger cAMP, and arachidonic acid (AA) derivatives.

Other Nonrenin Enzymes

Over the years, several renin-like enzymes were postulated to release Ang I from either AGT or the model synthetic substrate tetradecapeptide angiotensin-(1-14) (Ang-[1-14]). Cathepsin D and cathepsin G, acid and neutral proteases, tonin, the serine protease Esterase B, kallikrein-like serine proteases, and mouse gamma-nerve growth factor (γ-NGF) are among the enzymes implicated as Ang l-forming enzymes. Tonin forms Ang II directly from a plasma protein, from the tetradecapeptide substrate Ang-(1-14), and from Ang I. Tonin is present in most tissues, but in highest concentration it is found in submaxillary glands. A neutral protease with Ang l-forming activity that could readily be separated from acid proteases and both plasma and renal renin was identified in the dog brain. Findings of extended forms of Ang I, Ang-(1-25), and the dodecapeptide angiotensin-(1-12) in human and rodents raise additional issues as to whether nonrenin mechanisms may be more critical than anticipated previously.

Angiotensinogen

This 452-amino acid protein is the only known forming precursor of angiotensin peptides. The liver is the primary site for its synthesis, although in more recent years extrahepatic sources of generation exist in visceral fat, renal tubules, brain, heart, and reproductive organs. The AGT protein is produced through the cleavage of a single gene pre-pro-AGT (see Table 5.1 ). Synthesis, processing, and glycosylation changes vary in relation to species and site of tissue generation. The levels of the AGT protein are influenced by glucocorticoids, estrogen, thyroid hormone, insulin, and Ang II. A positive feedback in which Ang II augments AGT production has been demonstrated in the kidney and the liver. This mechanism may act to prevent depletion of substrate during excess Ang II production. On the other hand, Ang II reduces AGT mRNA in adrenal glands. Genetic studies underscore the critical role for the substrate in contributing to hypertension pathogenesis. Studies in transgenic mice show that arterial pressure increases in proportion to the number of AGT gene copies. Likewise, deletion of the AGT gene is associated with lower resting blood pressure, while the Lu et al. recent study shows that hypo-expression of the gene in a low-density lipoprotein receptor ^−/− background is associated with reduced blood pressure, less atherosclerosis, decreased body weight gain, and liver steatosis. Emerging evidence regarding an interplay among radical oxygen species (ROS), inflammation, and Ang II is strengthened by the observation that oxidative stress exposes the cleavage site of the AGT molecule to renin. Single nucleotide polymorphisms (SNPs) in the AGT gene have been explored for hypertension linkage. Data suggest that T174 and M235T associates with hypertension. We showed that genetic variation of the M235T, but not the ACE (I/D), genotype contributes to the presence of coronary heart disease independently of blood pressure.

Angiotensin I and II Forming Enzymes

The past decade has forced a revision of accepted tenets regarding the enzymatic pathways forming Ang II and other biologically active renin angiotensin system peptides. The classic view that ACE (EC 3.4.15.1) is the critical enzymatic fulcrum for the generation of Ang II has been challenged by the finding that chymase (CMA1; EC 3.4.21.39) forms Ang II directly from Ang-(1-12). Neprilysin and thimet oligopeptidase (EC 3.4.24.15) cleave Ang I to produce Ang-(1-7) in the circulation, while renal neprilysin generates Ang-(1-7) from either locally contained Ang-(1-12) or Ang I. Less appreciated are potential roles of (a) carboxypeptidase A (EC 3.4.17) forming angiotensin-(1-9) from Ang-(1-12) or Ang-(1-7) from Ang II; and (b) the Ang II generating ability of elastase-2 (EC 3.4.21.37). The variety of alternate pathways for angiotensin peptide formation may explain the failure to sustain Ang II suppression in patients chronically dosed with effective amounts of ACE inhibitors. The importance of these alternate pathways, primarily at the tissue level, may explain why the actual quantitative reduction in cardiovascular endpoints obtained with this drug class is less than predicted on the basis of their mode of action and physiological actions.

Angiotensin-Converting Enzyme

Renin catalytic action on human AGT generates angiotensin I (Ang I) through the cleavage of the amino acid bond between leucine and valine at positions 10 and 11. ACE, a di-carboxy peptidyl peptidase with a molecular weight of 150 to 180 kDa, cleaves Ang I to generate Ang II by removing the last two amino acids of the decapeptide (see Table 5.1 ). Although the role of ACE in forming Ang II was first identified by Skeggs, Marsh, Khan, and Shumway in 1954, recognition of its critical role in the renin angiotensin system cascade awaited the development of the solid-phase method of peptide synthesis by Merrifield in 1964. Ng and Vance’s identification of the lung as a critical physiological locus for the processing of circulating Ang I into Ang II set the stage for the development of ACE inhibitors, the first landmark clinically successful approach to blockade of the renin angiotensin system.

ACE can act on other substrates, including bradykinin, substance P, and the tetrapeptide N-acetyl-Ser-Asp-Lys-Pro (Ac-SDKP). ACE-mediated inhibition of bradykinin and Ac-SDKP metabolism are implicated in contributing to the mode of action of ACE inhibitors through potentiation of bradykinin vasodilator responses or antifibrotic mechanisms. The occurrence of angioedema, a side effect of ACE inhibitors more frequent in women and black patients, has also been linked to prevention of bradykinin and substance P metabolism.

ACE is ubiquitously found in cardiovascular tissues, primarily expressed in epithelial and endothelial cells. ACE activity found in blood, lymph, and cerebrospinal fluid represents a form of the enzyme that has lost its anchoring to the cell’s membranes by the cleavage of its C-terminus hydrophobic region. The process accounting for the shedding of ACE from the vascular endothelium remains to be characterized. Recently, lysozyme and bilirubin have been identified as contributing to ACE-shedding. Another feature of ACE that bears importance for its role within the renin angiotensin system arises from the fact that its extracellular loop contains two catalytic sites termed the C- and N-domains. While the catalytic activity of the C-domain has been linked to the processing of Ang I into Ang II, the N-domain cleaves Ang-(1-7) into Ang-(1-5).

The variety of substrates on which ACE can express its hydrolytic activity implicate its role in the regulation of multiple organ and cellular functions. Since human kidneys contain large proportions of ACE compared with other organs other than the lung, it has been argued that renal ACE-mediated Ang II formation acts as a master switch in the control of nephron sodium transport and the development of hypertension.

Chymase

Chymases are a group of chymotrypsin-like serine proteinases that have multiple functions in tissue injury and remodeling. Phylogenetic studies have divided chymases into two isoenzyme groups, α and β. An α-chymase gene has been identified in all mammals, including humans, while β-chymases exist only in several rodent species. β-Chymases are not expressed in humans. This is an important distinction because α-chymase forms Ang II, while β-chymases can both form and degrade Ang II. Chymase is elaborated by mast cells, vascular endothelial cells, and other interstitial cells within the human heart. The identification of other cellular sources, including cardiac fibroblasts and vascular endothelial cells, demonstrates a more widely dispersed production and distribution system that accounts for its relatively high protein abundance (about 1.3 μg/g in human heart tissue). Evidence for its intracellular presence in cardiomyocytes in the human heart opens an entirely new compartment of chymase-mediated actions that were previously thought to be limited to the extracellular space.

Chymase is 20 times more catalytically efficient than ACE in Ang I conversion to Ang II in the human heart. With ACE largely located on endothelial cells with its catalytic site exposed to the vascular lumen and chymase activity largely located in tissue, there is a compartmentalization of ACE- and chymase-mediated Ang II formation in the tissue and vascular space. The presence of chymase in tissue has been invoked in the mechanism of “ACE escape” and in a more indirect means through ACE inhibitor increase in bradykinin, causing mast cell degranulation and chymase release. Most recently, AGT has been shown to be a substrate for Ang-(1-12) generation in the human heart that is independent of renin and ACE.

In addition to its very potent Ang II-forming capacity, chymase protease actions also mediate cleavage of matricellular proteins and peptides, including laminin and fibronectin, important in cell survival; chymase activates peptide and enzyme precursors including matrix metalloproteinases (MMPs), transforming growth factor-β (TGF-β), stem cell factor (SCF) (causing further mast cell degranulation and chemotaxis), interleukin-6 (IL-6) and IL-1β, and conversion of pre-pro-endothelin I (pre-proET1). All these mechanisms of action are crucial factors in cardiovascular injury and remodeling (see also Chapter 1, Chapter 2, Chapter 4, Chapter 12 ). Taken together, chymase mediates a critical balance of (1) profibrotic ET-1 and Ang II formation, myofibroblast formation, and TGF-β activation; (2) antifibrotic protease activation of MMPs, direct digestion of matricellular proteins, and formation of bradykinin (BK); and (3) inflammatory cytokines and SCF activation and chemotaxis of inflammatory cells. These multiple protease actions in addition to its Ang II-forming capacity are complemented by chymase upregulation in the human myocardial infarction heart and vulnerable atherosclerotic plaque, aortic aneurysm, atherosclerosis, and diabetic kidney.

Angiotensin-Converting Enzyme 2

ACE2 is a type 1 integral membrane glycoprotein that functions as a mono carboxypeptidase–converting Ang I into Ang-(1-9) and Ang II into Ang-(1-7). The affinity of the enzyme for Ang-(1-7) formation from Ang II is higher than its affinity for Ang I. Although ACE2 is a close ACE homologue, ACE2 catalytic activity is not blocked by drugs that inhibit ACE. Like many other enzymes, ACE2 displays hydrolytic activity for other proteins such as vasoactive bradykinin (1–8), des-Arg-kallidin, Apelin-13, and Apelin-36. Additional features of the enzyme include 48% sequence identity with collectrin at the noncatalytic C-terminal domain of the enzyme and the demonstration that ACE2 is the receptor for SARS virus. While ACE2 is most abundant in heart, kidney, the retina, and the utero-placenta complex, a secreted form of ACE2 generated from the hydrolytic activity of a disintegrin and metalloprotease domain 17 (ADAM17) is present in blood.

The Crackower et al. landmark study demonstrated ACE2’s role in the regulation of cardiac function. That Ang II influenced ACE2 gene expression in the heart provided evidence for the existence of a regulatory control of Ang II expression by the opposing actions of ACE as an Ang II-forming enzyme versus the ACE2 Ang II-degrading mechanism. Additional studies directed to understand the signaling mechanisms by which Ang-(1-7) acts as a negative regulator of Ang II actions identified a primary role of ACE2 in the formation of the heptapeptide from Ang II in the heart. These studies showed that cardiac overexpression of ACE2 reversed cardiac hypertrophy in SHR, identified the mas receptor as the site at which Ang-(1-7) acts to inhibit myocyte hypertrophy, demonstrated a role of ACE2 in modulating the central neurogenic actions of Ang-(1-7), and revealed a critical role of the ACE2/Ang-(1-7)/mas-receptor axis in the regulation of fetal development and pregnancy. These data now constitute the foundation for a more precise mechanistic analysis of the biological and signaling processes by which the ACE2/Ang-(1-7)/mas receptor axis counteracts the actions of Ang II on blood pressure, cardiac and vascular remodeling, and metabolic and renal function.

Other Angiotensin-Forming Enzymes

Because proteolytic enzymes participate in multiple regulated cellular processes, alternate biotransformation pathways within the renin angiotensin system need not be restricted to classic canonical and non-canonical pathways. The molecular basis for the effector hormonal and tissue actions of angiotensins in maintaining the normalcy of the internal environment transcends their function in the control of fluid volumes and tissue perfusion. The tissular actions of Ang II as a growth factor, a stimulant of fibrosis, and its prothrombotic mechanisms need not be identical in the heart, brain, kidneys, and bone marrow. The demonstration of the existence of renin angiotensin system genes in the intracellular environment need not reflect a functional processing of biologically active angiotensins through enzymatic pathways previously characterized in the circulation or even the extracellular compartments. Ang II participation in innate and adaptive immune mechanisms, modulation of hematopoiesis, and progenitor cell expression and function may result from biochemical biotransformation of precursor peptides where neither renin nor ACE play a role. In the context of this discussion, emerging studies demonstrating novel roles for carboxypeptidase A and B (see Table 5.2 ), elastase, cathepsin G, proteinase 3, caspase-1, and chymase in angiotensin peptide metabolism or processing of inflammatory cytokines such as IL-1β deserve future attention.

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