Non-ACE Pathway-induced Angiotensin II Production

Abstract

For the past century, the renin-angiotensin system (RAS) has been recognized as one of the major blood pressure-regulating systems. Angiotensin II (Ang II) is the final physiologically active product of RAS, and it works not only as a strong vasopressor but also as a promotor of tissue remodeling in various organs such as heart, arteries, and kidneys. RAS is the predominant pathway of Ang II formation in human plasma, but not in the tissues. There are several alternative pathways producing angiotensin II in human tissues, and they are involved in structural remodeling of the cardiovascular system. Proteinases such as chymase, kallikrein, cathepsin G, and elastase-2 are probably responsible for angiotensin-converting enzyme (ACE)-independent Ang II formation in human tissues. In particular, chymase is an important Ang II-generating enzyme in the human heart. It is important to elucidate the mechanisms of the ACE-independent Ang II formation in human tissues; long-term inhibition of the local Ang II formation may become one of the strategies to prevent cardiovascular remodeling.

Angiotensin-(1–7) treatment mitigates right ventricular fibrosis as a distinctive feature of diabetic cardiomyopathy

“…Paradoxically, despite reduced ACE activity in ANG-(1-7)-treated right ventricles, ANG-II level remained high (data not shown), which suggests that other enzymes or pathways besides ACE may be involved in the formation of ANG-II. One such candidate is chymase, which has been detected in cardiac and vascular tissues (29). Consistent with previous results of a model of pulmonary fibrosis induced by bleomycin (23), we first demonstrated that ANG-(1-7) treatment downregulated the level of AT 1 receptor and upregulated that of AT 2 receptor in diabetic RV tissues.…”

Efficiency Evaluation of the Combination Therapy for Comorbid Arterial Hypertension with Diabetes Mellitus 2 Type Depending on the Genetic Polymorphism of the Angiotensin-Converting Enzyme

“…Крім нирок настільки висока актив-ність локальної РААС виявлена при ЦД у серці і ендотелії судин. Надмірне утворення АТ II в нирках веде до внутрішньоклубочкової гіпертензії, потім до склерозу і фіброзу ниркової тканини, у серці -до ремоделювання міокарду, в судинах сприяє розвитку атеросклерозу [12]. Дослідження останніх років показали, що гіперактивність РААС грає важ-ливу роль в розвитку інсулінорезистентності (ІР), що в свою чергу може привести і до ЦД 2 типу [9].…”

“…Компоненти локаль-ної РААС виявлені як в екзокринних протоках, так і в b-клітинах острівців підшлункової залози. Це до-зволило пояснити блокуючу дію АТ II на секрецію інсуліну і посилення ІР периферійних тканин при його надмірній секреції [2,12].…”

A Review on the Role of Chymase in Hypertensive Heart Disease

“…This further bolsters the presence of an Angiotensin Converging Enzymes (ACE)-independent pathway in angiotensin-II formation. In the last two decades, the activity of alternate pathways mediating the conversion of angiotensin-I to angiotensin-II were discovered [16], challenging renin-angiotensin-aldosterone system as the sole pathway. The raveling of an alternate pathway was discovered by Cornish and colleagues in 1978, who reported the existence of a possible alternate pathway in angiotensin-II formation in animal models [12].…”