Cardiovascular Drugs and Therapy

, Volume 27, Issue 2, pp 139–143

Chymase Inhibition and Cardiovascular Protection

Authors

  • Hideaki Tojo
    • Department of Cardiovascular DiseasesFukuoka University Chikushi Hospital
    • Department of Cardiovascular DiseasesFukuoka University Chikushi Hospital
REVIEW ARTICLE

DOI: 10.1007/s10557-013-6450-4

Cite this article as:
Tojo, H. & Urata, H. Cardiovasc Drugs Ther (2013) 27: 139. doi:10.1007/s10557-013-6450-4

Abstract

Human chymase, an angiotensin II-forming chymotrypsin-like serine proteinase, posses various biological actions mediating through local angiotensin II formation in the tissue level of many cardiovascular organs. Our previous experimental data have shown that chymase inhibitor increased a survival rate of the hamster post-myocardial infarction model with concomitant improvements of the cardiac function and hypertrophy, decreased hamster aortic atherosclerotic lesion induced by a high fat diet and improved hamster diabetic nephropathy decreasing the proteinuria and increased renal antiotensin II levels. Although chymase inhibitor has not yet been applied for clinical use, clinical cardiovascular diseases above mentioned appear to be the target of chymase inhibitor. The related basal and clinical circumstances are discussed in this review article for chymase inhibitor.

Keywords

angiotensin IIserine proteinaselocal renin-angiotensin system

Introduction

Angiotensin II (Ang II), the biologically potent effector hormone of the renin-angiotensin system (RAS), has various neurohormonal effects, including hypertensive vasoconstriction, promotion of interstitial fibrosis, increasing cytokine production, and promoting aldosterone release [1]. Besides the vascular RAS, the role of the tissue RAS has come to be emphasized because each RAS component (including angiotensinogen, renin, ACE, chymase, and the angiotensin receptor) has been identified in the tissues of organs such as the heart, kidney and vasculature [2]. In addition, there is a discrepancy between the activity and levels of the vascular and tissue RAS component under certain circumstances. For instance, many studies have demonstrated that the tissue concentration of Ang II is much higher than its concentration in the blood, indicating that the main actions of Ang II may be mediated at the tissue level rather than in the circulation [3].

Enzymes Involved in Ang II Formation

Ang II is formed from Ang I by ACE, chymase, or cathepsin G, while it is produced from angiotensinogen by cathepsin G or kallikrein [4]. These enzymes involved in Ang II formation are abundant in many tissues, so any Ang I is produced at the tissue level is immediately converted into Ang II. Chymase and cathepsin G are serine proteinases. As these enzymes are inactivated in the blood by serine proteinase inhibitors, such as alpha 1 antitrypsin and alpha 2 macroglobulin, they are only active at the tissue level. In order to reduce the tissue concentration of Ang II, it is important to inhibit tissue renin or ACE activity as well as inhibiting these Ang II-forming serine proteinases.

Pathophysiological Role of ACE-Independent Ang II Formation by Serine Proteinases

The chymase activity in human cardiovascular tissues is significantly higher than the tissue ACE activity [5]. Therefore, ACE inhibitor therapy cannot reduce tissue Ang II levels as effectively as it does in the blood [6]. On the other hand, angiotensin receptor blockers (ARBs) suppress the effects of Ang II produced by tissue chymase and other non-ACE enzymes. Consequently, it has been suggested that ARBs should provide better organ protection than ACE inhibitors. However, a number of clinical trials comparing the effects of ARBs and ACE inhibitors have failed to show any superiority of the former, although the non-inferiority of ARBs relative to ACE inhibitors has been proved [7, 8]. Thus, ARBs show similar efficacy to ACE inhibitors for reducing mortality and morbidity in hypertensive patients with cardiovascular disease, but why this is so remains unclear. Ang II produced by chymase in patients on ARB therapy should stimulate the AT2 receptor, which has been shown to be a beneficial receptor in a series of studies performed in AT2 receptor knockout mice [9]. Therefore, treatment with ARBs should achieve a better outcome than ACE inhibitor therapy if the blood pressure achieved with both drugs is similar.

Interestingly, treatment of hypertension or heart failure with a combination of an ARB and an ACE inhibitor achieves a worse outcome than monotherapy with either class of drug [8]. The results obtained by large-scale clinical studies do not indicate any definitive benefit of the AT2 receptor, although such a strategy may be beneficial in diabetic nephropathy as ARB therapy has been shown to achieve an improved outcome in this disease [10, 11]. In these studies, compared with the control treatment, ARB therapy decreased microalbuminuria, slowed the advance of renal dysfunction, and decreased progression to end-stage kidney disease. A recent experimental study in mice also indicated a beneficial effect of the AT2R after cerebral infarction, since AT2R KO mice developed larger infarcts compared with control mice following middle cerebral artery ligation [12].

Pathological Effects of Ang II Formation by Chymase

Our previous clinical research has revealed that non-ACE Ang II formation, particularly that due to chymase, is upregulated in aortic atherosclerotic lesions including aneurysmal tissue [13], in the ventricular myocardium after myocardial infarction [14], and in the internal thoracic artery of patients with elevated LDL-C levels [15]. Histological examination has provided evidence that this upregulated tissue chymase activity is due to the release of chymase from mast cells in response to both acute and chronic stimuli. An acute post-MI response has also been observed for circulating mononuclear leukocytes (CML), including lymphocytes and monocytes, containing definitive levels of chymase activity [16]. The level of chymase activity in CML is about 3-fold higher in patients at 1 day after MI compared with that in patients who were admitted with other cardiovascular diseases [17]. We have also analyzed the myocardium at 14–21 days after MI and have found that chymase activity was higher than that of other Ang II-forming enzymes such as ACE or cathepsin G [14]. These results indicate that pathological stress such as infarction or ischemia caused by acute coronary syndrome induces an acute increase of Ang II-forming activity in circulating CML, and subsequent migration of these leukocytes into the myocardium increases tissue levels of Ang II-forming activity and leads to post-MI cardiac remodeling. In fact, our previous animal study using a hamster model of MI revealed that treatment with a chymase inhibitor suppresses post-MI remodeling and improves survival (Fig. 1g) [18, 19].

Clinical Targets for Chymase Inhibitors

A number of orally active chymase inhibitors have been developed, but none of them has yet been applied clinically. However, several important animal studies have shown various beneficial effects of chymase inhibitors on cardiovascular disease, including the inhibition of post-MI cardiac remodeling with a resultant improvement of survival (as mentioned above) [18], suppression of myocardial fibrosis in hypertensive cardiac hypertrophy [20], inhibition of the development of atherosclerotic lesions in hamsters on a high fat diet [21], and dramatic improvement of glycemic control and renal impairment in a hamster model of type I diabetes [22].

Syrian hamsters have alpha-chymase, which produces Ang II from Ang I and does not degrade the Ang II that it produces, whereas beta-chymase in rats simultaneously degrades Ang II as it is produced, so beta-chymase is not an Ang II-forming enzyme [23]. This means that the Syrian hamster is a more appropriate model for studies on the effects of chymase [24].

Ischemic Heart Disease

Using a hamster MI model, Hoshino et al. examined the effect of chymase inhibitor monotherapy on post-MI survival [18] and found significant improvement. In addition, combined treatment with a chymase inhibitor and an ACE inhibitor improved survival significantly compared to monotherapy with either agent (Fig. 1g), suggesting that Ang II formation by ACE and chymase influences the prognosis of post-MI hamsters [25]. In fact, in vivo cardiac function parameters were improved in the combined treatment group compared with either monotherapy group (Fig. 1a–f) [25]. It is possible that an increase of bradykinin due to ACE inhibitor treatment stimulates chymase expression and activity in the heart, thus weakening the beneficial effect of ACE inhibitor therapy. Thus, the combination of a chymase inhibitor and an ACE inhibitor appears to be superior in the post-MI state. Since ACE inhibitor monotherapy has already been proved to be beneficial after MI in many clinical studies, addition of a chymase inhibitor might be expected to provide an additional benefit.
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Fig. 1

Effect of an ACE inhibitor, a chymase inhibitor, or combination therapy on LV function, cardiomyocyte size, interstitial fibrosis, infarct size, and survival in hamsters after MI. EF (a), FS (b), average cardiomyocyte diameter (c), LV interstitial fibrosis (d), infarct area (e), andLV end-diastolic dimension (f) in MI hamsters treated with the vehicle (MI), an ACE inhibitor (temocapril, 10 mg/kg/d) (ACEI), a chymase inhibitor (CI-B, 100 mg/kg/d) (CI), or combination therapy (temocapril (10 mg/kg/d) + CI-B (100 mg/kg/d)) (ACEI + CI) for 34 days starting from 24 h after MI or sham operation. g Actual survival of hamsters with MI following treatment with the vehicle, an ACE inhibitor, a chymase inhibitor, or combination therapy, or after sham operation. Values are the mean ± SEM. Values in parentheses show the number of animals in each group. *P < 0.05; **P < 0.01; ***P < 0.001 [19]

Atheromatous Disease

In a hamster model of atherosclerosis induced by feeding a high-fat diet for 14 weeks, treatment with a chymase inhibitor decreased atheromatous lesions in the aortic valve area [21]. Therefore, monotherapy with a chymase inhibitor may be effective for decreasing atheroma. Several previous studies have shown that upregulation of chymase is linked with an increase of atherogenic cytokines such as TGF-beta, as well as with the activation of IL-1 precursor and formation of big endothelin.

Diabetes Mellitus

In a hamster model of type I diabetes induced by streptozotocin, renal chymase expression was markedly upregulated. Oral administration of a specific chymase inhibitor completely abolished proteinuria (Fig 2b), glomerular overexpression of transforming growth factor-beta and fibronectin, and renal mesangial expansion by normalizing the renal tissue levels of chymase and angiotensin II independently of its influence on blood pressure (Fig. 2a). In contrast, ramipril did not show any of these effects.
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Fig. 2

Effect of chymase inhibitors and ramipril on serum and intrarenal ANG II levels. White bars: nondiabetic control hamsters (control). Black bars: hamsters with STZ-induced diabetes (STZ). a intrarenal AngII content after 8 weeks of treatment. Values are the mean ± SE. Nonsignificant p values are not indicated.*p < 0.05, **p < 0.01 (ANOVA). b and c Effect of chymase inhibitors and ramipril on renal damage. White bars: nondiabetic control hamsters (control). Black bars: hamsters with STZ-induced diabetes (STZ). b Urinary protein excretion adjusted for 24-h urine volume (ml) and body weight after 4 and 8 weeks of treatment. Values are the mean ± SE. Nonsignificant p values are not indicated. *p < 0.05, **p < 0.01 (ANOVA).c Periodic acid-Schiff (PAS) staining of hamster kidneys [22]

Conclusion

Clinical application of chymase inhibitor therapy has not yet been achieved, but the pathological conditions mentioned in this article might be targets for such treatment in the near future, although clinical trials would be necessary to clarify the efficacy of chymase inhibitors.

Copyright information

© Springer Science+Business Media New York 2013