Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The sympathetic nervous system, coronary artery disease and myocardial ischaemia are related in different ways. First, the sympathetic system may be involved in the process of atherosclerosis through platelet activation and subsequent platelet-derived growth factor formation and by inducing mechanical injury to the vascular wall as a result of increased blood pressure and increased flow velocity. Secondly, sympathetic control of coronary vasomotor tone, which under normal conditions is not important, becomes functionally significant once coronary artery disease endothelial dysfunction has occurred. Under these circumstances, increased sympathetic adrenergic tone may lead to coronary vasoconstriction and, as myocardial oxygen demand increases concomitantly, myocardial ischaemia may ensue. Alternatively, myocardial ischaemia activates several neurohormonal systems, such as the sympathetic and, during more severe ischaemia, the circulating renin-angiotensin system. This leads to systemic and, possibly, coronary vasoconstriction and thus to further myocardial ischaemia. Prolonged myocardial ischaemia results in progressive norepinephrine release from the heart, reaching extracellular levels as high as 100-1000 x plasma concentrations. As cardiac beta-receptor density rises simultaneously, sympathetically-induced irreversible myocardial damage may occur, although through concomitantly increased beta-receptor kinase activity the beta-receptor may become functionally inactive. To counteract the detrimental effects of enhanced sympathetic activation on the heart, beta-blockade appears to be the proper choice. However, acute beta-blockade may lead to more profound ischaemia-induced neurohormonal activation and hence to vascular constriction through unoccupied alpha-receptors. In contrast, under ischaemic conditions and with concomitant beta-blockade, acute alpha-blockade does improve subendocardial flow and reduces myocardial ischaemia. A novel approach to anti-ischaemic therapy, which relates to modulating ischaemia-induced sympathetic activation, is through ACE inhibition. ACE inhibitors affect myocardial ischaemia by reducing neurohormonal activation and related systemic and coronary vasoconstriction. These acute effects may become more important over time, as coronary endothelial function improves following long-term ACE inhibition. A large multicentre controlled trial comparing ACE inhibition with placebo in patients with coronary artery disease, the EUROPA (EUopean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease), which is currently underway, addresses the issue of whether ACE inhibition does in fact offer a novel approach in myocardial ischaemia.
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PMID:The sympathetic nervous system and ischaemic heart disease. 965 38

To elucidate the contribution of the renin-angiontensin system (RAS) to glomerular injury in salt-sensitive hypertension, we investigated the chronic effects of the angiotensin I-converting enzyme inhibitor cilazapril and the angiotensin II type 1-receptor antagonist (AT1a) TCV-116 in Dahl-Iwai rats. Dahl salt-sensitive (S) rats receiving 8% salt diet for 6 wk were simultaneously treated with cilazapril (n = 6), TCV-116 (n = 6), or saline (n = 14). The 8% salt diet markedly increased systolic blood pressure (SBP), urinary protein, and N-acetyl-beta-glucosaminidase (NAG) excretion compared with 0.3% salt-treated S (n = 6) or salt-resistant (n = 6) rats. Although neither cilazapril nor TCV-116 reduced the elevated SBP, TCV-116 significantly lowered urinary protein and NAG excretion. Histologically, 8% salt treatment in S rats induced progressive sclerotic and proliferative glomerular changes, which were ameliorated by both drugs. TCV-116 increased the glomerular diameter. Immunofluorescence demonstrated the increased level of type III collagen in the mesangium of 8% salt-treated S rats, which was completely reversed by TCV-116. Competitive RT-PCR of mRNA extracted from the glomeruli revealed that 8% salt treatment significantly increased the levels of proliferating cell nuclear antigen (PCNA) and platelet-derived growth factor B-chain and that TCV-116 significantly reduced the levels of PCNA and transforming growth factor-beta1 (TGF-beta1). Thus, although the chronic RAS-inhibition in salt-sensitive hypertension exerted a histologically renoprotective effect by both ways without lowering blood pressure, the RAS inhibition due to AT1a had more beneficial advantages of reducing proteinuria and attenuating the levels of glomerular TGF-beta1 and extracellular matrix.
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PMID:Effects of chronic inhibition of ACE and AT1 receptors on glomerular injury in dahl salt-sensitive rats. 984 88

We previously demonstrated remodeling of large and small arteries in angiotensin II-treated rats, paralleled by an increased expression of platelet-derived growth factor (PDGF)-A chain mRNA in large arteries. Both remodeling and PDGF-A expression were associated with elevation of blood pressure rather than a direct effect of angiotensin II. To further delineate the role of PDGF-A and elevated blood pressure, we assessed the level of PDGF-A and -B mRNA and protein in the wall of large as well as small arteries in the one-kidney, one-clip (1K1C) hypertensive rat, a non-renin-dependent model of hypertension. Fourteen days after renal artery stenosis, the thoracic aorta and both femoral arteries were collected from 1K1C rats (n = 8) and uninephrectomized controls (n = 8) and immediately processed for morphological measurement, immunohistochemistry, RT-PCR, and Western blotting. Systolic blood pressure was significantly elevated in hypertensive rats (202 +/- 26 mmHg) compared with control rats (122 +/- 7.9 mmHg) and was accompanied by arterial hypertrophy in both aorta and femoral arteries. The mRNA for PDGF-A chain was increased threefold in the thoracic aorta (P < 0.05) of 1K1C rats, whereas the message for PDGF-B was not significantly changed in hypertensive versus control animals. A higher staining of the intima-media was observed by using an anti-PDGF-A chain polyclonal antibody on paraffin-embedded sections. Western blot results indicated an approximately 2-fold increase in PDGF-A protein in aortic and femoral wall of the 1K1C rats. The results showed that both the mRNA and protein for PDGF-A chain are increased and well correlated with the blood pressure and wall area, suggesting a direct effect of elevated pressure on PDGF synthesis, which, in turn, may affect the onset and progression of vascular hypertrophy.
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PMID:PDGF-A expression correlates with blood pressure and remodeling in 1K1C hypertensive rat arteries. 1036

Angiotensin II plays a central role in the regulation of systemic arterial pressure through its systemic synthesis via the renin-angiotensin-aldosterone cascade. It acts directly on vascular smooth muscle as a potent vasoconstrictor. In addition, it affects cardiac contractility and heart rate through its action on the sympathetic nervous system. Angiotensin II also alters renal sodium and water absorption through its ability to stimulate the zona glomerulosa cells of the adrenal cortex to synthesize and secrete aldosterone. Furthermore, it enhances thirst and stimulates the secretion of the antidiuretic hormone. Consequently, angiotensin II plays a critical role in both the acute and chronic regulation of blood pressure through its systemic endocrine regulation. A potent neurohormone that regulates systemic arterial pressure, angiotensin II also affects vascular structure and function via paracrine and autocrine effects of local tissue-based synthesis. This alternate pathway of angiotensin II production is catalyzed in tissues via enzymes such as cathepsin G, chymostatin-sensitive angiotensin II-generating enzyme, and chymase. Intratissue formation of angiotensin II plays a critical role in cardiovascular remodeling. Upregulation of these alternate pathways may occur through stretch, stress, and turbulence within the blood vessel. Similar processes within the myocardium and glomeruli of the kidney may also lead to restructuring in these target organs, with consequent organ dysfunction. Additionally, angiotensin II may increase receptor density and sensitivity for other factors that modulate growth of vascular smooth muscle, such as fibroblast growth factor, transforming growth factor beta-1, platelet-derived growth factor, and insulin-like growth factors. Atherosclerosis may also be related, in part, to excessive angiotensin II effect on the vessel wall, which causes smooth muscle cell growth and migration. It also activates macrophages and increases platelet aggregation. Angiotensin II stimulates plasminogen activator inhibitor 1 and directly causes endothelial dysfunction. Other postulated effects of angiotensin II on vascular structure that could promote atherogenesis include inhibition of apoptosis, increase in oxidative stress, promotion of leukocyte adhesion and migration, and stimulation of thrombosis. Inhibition of angiotensin II synthesis with an angiotensin-converting enzyme inhibitor has been demonstrated to be beneficial in modifying human disease progression. This is clearly apparent in clinical trials involving patients with diabetic nephropathy, postmyocardial infarction, or advanced degrees of systolic heart failure. Thus, angiotensin II is an excellent target for pharmacologic blockade. Not only does it play a pivotal role in both the acute and chronic regulation of systemic arterial pressure, but it also is an important modulator of cardiovascular structure and function and may be specifically involved in disease progression. Modification of angiotensin II effect may therefore serve a dual purpose. Not only will blood pressure reduction occur with less stretch, stress, and turbulence of the vascular wall, but there will also be less stimulation, either directly or indirectly, for restructuring and remodeling of the cardiovascular tree.
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PMID:The renin-angiotensin-aldosterone system: a specific target for hypertension management. 1061 73

Previously, it was shown that 5/6 renal mass reduction by surgical excision (RK-NX) results in a marked reduction of glomerulosclerosis (GS) at 6 wk compared with the conventional 5/6 renal ablation by infarction (RK-I) model. To determine the pathogenetic correlates of the striking differences in GS, radiotelemetrically measured BP; single nephron function; glomerular volume; the temporal expression of mRNA for renin, transforming growth factor-beta, and platelet-derived growth factor-B; and plasma renin concentration were compared between RK-NX, RK-I, and sham-operated control rats. Hypertension only developed in the RK-I model, was present at 3 d after infarction, and was correlated with both an increased expression of renin mRNA by Northern analysis and elevated plasma renin concentration. Structural (glomerular volume) and functional (single nephron blood flow and GFR) indices of the compensatory adaptive response were significantly but similarly increased in the RK-NX and RK-I rats compared with sham-operated controls, indicating that these adaptations per se are not responsible for the initiation of GS after 5/6 renal mass reduction. Glomerular capillary pressure (P(GC)) was also significantly increased in both RK-I (56 +/- 2 mmHg) and RK-NX rats (50 +/- 0.9 mmHg) compared with controls (46 +/- 0.8 mmHg, P < 0.01), but the increase was significantly greater in RK-I versus RK-NX rats (P < 0.05) consistent with the higher BP in RK-I rats. These data indicate that differences in renin probably account for the early divergence of BP (and P(GC)) responses between RK-I and RK-NX models. Transforming growth factor-beta and platelet-derived growth factor-B mRNA expression in pooled RNA from kidneys from each group showed increases at 21 d along with early evidence of glomerular injury in the RK-I group but not in the RK-NX group, consistent with their postulated roles as molecular mediators of GS, but only in rats with pathologic glomerular hypertension.
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PMID:Functional and structural correlates of glomerulosclerosis after renal mass reduction in the rat. 1070 73

The expression of renin-angiotensin system components and the elevation of angiotensin-converting enzyme (ACE) in a number of fibrotic lung diseases suggests angiotensin II (AII) could play a role in the pathogenesis of pulmonary fibrosis. However, the effect of AII on lung fibroblasts has not previously been assessed and the mechanisms by which AII induces cell proliferation in mesenchymal cells are not fully understood. We have examined the ability of AII to stimulate fetal and adult human lung fibroblast proliferation in vitro. In particular, we have assessed the receptor subtypes involved and the possible autocrine role of transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF), two recognized fibroblast mitogens. Angiotensin type 1 (AT1), but not type 2, receptors were identified on fetal and adult human lung fibroblasts by immunocytochemistry. AII (1 microM) increased DNA synthesis (determined by [(3)H]thymidine incorporation) in fetal and adult cells by 211 +/- 18% and 150 +/- 14%, respectively (p < 0.01), and was inhibited by a specific AT1 receptor antagonist, Losartan (74 +/- 14%). A proliferative response to AII was confirmed by direct cell counts. Subsequently, fibroblasts were incubated with neutralizing antibodies to TGF-beta and PDGF. Anti-TGF-beta antibodies inhibited AII-induced DNA synthesis by 73 +/- 13%. However, no effect was seen with anti-PDGF antibodies. In conclusion, we have shown that angiotensin II induces human lung fibroblast proliferation in vitro via activation of the AT1 receptor and involves the autocrine action of TGF-beta.
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PMID:Angiotensin II is mitogenic for human lung fibroblasts via activation of the type 1 receptor. 1085 80

Angiotensin II (Ang II), an effector peptide of the renin-angiotensin system, has been reported to stimulate growth of blood vessels in vivo and smooth muscle cells in culture. In this study, the effect of Ang II on DNA synthesis was examined in deendothelialized human saphenous vein in organ culture. After 7 days' exposure to medium containing 0.4% fetal calf serum plus Ang II, there was a marked increase in DNA synthesis. The effect of Ang II was comparable to the response to platelet-derived growth factor. Responses to Ang II were partially inhibited by the AT(1) receptor antagonist candesartan. An AT(2) receptor antagonist, PD123319, had no effect on Ang II-induced DNA synthesis, either alone or in combination with candesartan. The Ang II peptide analogues [Sar(1), Ile(8)]-Ang II (saralasin) and [Sar(1),Thr(8)]-Ang II (sarthran) acted as agonists, increasing DNA synthesis. In the presence of saralasin, responses to Ang II were inhibited. Tyrphostin-23, a tyrosine kinase inhibitor, prevented Ang II-induced DNA synthesis and reduced DNA synthesis in tissues incubated in medium containing only 0.4% fetal calf serum. In conclusion, Ang II stimulates DNA synthesis in human saphenous vein in organ culture. The effect of Ang II was more marked than has been previously reported in isolated cultured saphenous vein smooth muscle cells, and this effect is mediated in part by an angiotensin type 1 receptor. It is possible that an undefined receptor for Ang II may also be involved in the stimulation of DNA synthesis in this preparation.
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PMID:Action of angiotensin II on DNA synthesis by human saphenous vein in organ culture. 1108 67

Angiotensin II (Ang II), the primary effector of the renin-angiotensin system, is a multifunctional hormone that plays an important role in vascular function. In addition to its classical vasoconstrictor action, more recent studies demonstrated that Ang II stimulates the growth of a number of cell types, including vascular smooth muscle cells (SMC) (reviewed in [1-3]). In vivo studies have shown that chronic infusion of Ang II leads to the development of vascular hypertrophy in rats, whereas administration of angiotensin-converting enzyme (ACE) inhibitors or Ang II receptor antagonists prevents or regresses vascular hypertrophy in models of genetic and experimental hypertension [4]. Consistent with in vivo data, several laboratories have shown that Ang II stimulates protein synthesis and induces cellular hypertrophy, but not cell proliferation, in cultured aortic SMC [5-9]. Ang II also induces directed migration (chemotaxis) of vascular SMC [10, 11], although its effect is less prominent than that of platelet-derived growth factor (PDGF). The cellular mechanisms underlying these diverse actions of Ang II are not clearly understood but are likely to involve the activation of distinct signaling pathways.
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PMID:Functional cross-talk between the cyclic AMP and Jak/STAT signaling pathways in vascular smooth muscle cells. 1110 41

Angiotensin II induces the expression of platelet-derived growth factor A-chain and B-chain in cultured vascular smooth muscle cells at the level of transcription. The renin-angiotensin system has also been implicated in the increased expression of platelet-derived growth factor in the mechanically-injured artery wall. This review is concerned with recent developments in our understanding of the signaling and transcriptional mechanisms mediating the inducible expression of one vasoconstrictor by another.
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PMID:Mechanisms of angiotensin II-induced platelet-derived growth factor gene expression. 1110 50

Aldosterone is implicated in cardiac hypertrophy and fibrosis. We tested the role of the mineralocorticoid receptor in a model of angiotensin II-induced cardiac injury. We administered spironolactone (SPIRO; 20 mg. kg(-1). d(-1)), valsartan (VAL; 10 mg. kg(-1). d(-1)), or vehicle to rats double transgenic for the human renin and angiotensinogen genes (dTGR). We investigated basic fibroblast growth factor (bFGF), platelet-derived growth factor, transforming growth factor-beta(1), and the transcription factors AP-1 and nuclear factor (NF)-kappaB. We used immunohistochemistry, electrophoretic mobility shift assays, and TaqMan RT-PCR. Untreated dTGR developed hypertension, cardiac hypertrophy, vasculopathy, and fibrosis with a 50% mortality rates at 7 weeks. SPIRO and VAL prevented death and reversed cardiac hypertrophy, while only VAL normalized blood pressure. Both drugs prevented vasculopathy. bFGF was markedly upregulated in dTGR, whereas platelet-derived growth factor-B and transforming growth factor-beta(1) were little changed. VAL and SPIRO suppressed this upregulation. Both AP-1 and NF-kappaB were activated in dTGR compared with controls. VAL and SPIRO reduced both transcription factors and reduced bFGF, collagen I, fibronectin, and laminin in the interstitium. These findings show that aldosterone promotes hypertrophy, cardiac remodeling, and fibrosis, independent of blood pressure. The effects involve AP-1, NF-kappaB, and bFGF. Mineralocorticoid receptor blockade downregulates these effectors and reduces angiotensin II-induced cardiac damage.
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PMID:Mineralocorticoid receptor affects AP-1 and nuclear factor-kappab activation in angiotensin II-induced cardiac injury. 1123 Mar 74


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