The Central Role of Angiotensin I-Converting Enzyme in Vertebrate Pathophysiology

Abstract

Genomic epidemiologic data, increasingly supported by clinical outcomes results, strongly suggest that overactivity of angiotensin I-converting enzyme (ACE) may underlie most age-related diseases. Angiotensin II, the main product of ACE, is a pleiotropic hormone, capable of serving as a neurotransmitter, growth factor, angiogenesis factor, vasoconstrictor, pro-thrombotic agent, and cytokine. So it is perhaps not surprising that the ACE D/D genotype is associated with several major psychiatric diseases, most cancers except prostate cancer (where the D/D genotype is actually protective), most cardiovascular diseases, most autoimmune diseases, and even infectious diseases like tuberculosis and HIV. In a preliminary study, angiotensin II blockade appeared to hasten recovery from West Nile virus encephalitis; it may be equally useful in SARS. The ACE gene underwent duplication at the origin of Chordata, just before the "Cambrian Explosion" in the number of species. The ancestral, unduplicated form of ACE is still expressed during the terminal differentiation of human spermatocytes, suggesting a critical role in reproduction. The crystal structure of testicular ACE (tACE) was recently published. Computer modeling suggests that tACE may be activated by both mechanical forces and reducing agents. The duplicated form of ACE (somatic ACE, sACE) is expressed in areas of high fluid flow. sACE may auto-dimerize via a novel protein motif, the "disulfide zipper." The sACE dimer is predicted to have higher catalytic efficiency and redox resistance than tACE.

Antiproliferative Efficacy of Angiotensin II Receptor Blockers in Prostate Cancer

“…Although the survival of patients with chemotherapyresistant pancreatic cancer is less than four months and cachexia is common, once she began taking quinapril, her appetite improved dramatically, and her condition remained excellent for 12 months. Furthermore, her CA-19 level dropped steadily to a nadir of 394 U/ml, seven months after starting quinapril [104]. This phenomenon is similar to our experience with ARB treatment for HRPC patients, and ACE inhibitors and ARBs appear to exert their anticancer effects on cancer cells by similar mechanisms.…”

“…Ang-II is a potent cytokine, which can induce the synthesis of inflammation-related cytokines, macrophage migration inhibition factor (MIF), TNFα, monocyte chemoattractant protein-1 (MCP-1) and TGFβ etc. [104]. The AT1 receptor, a component of RAS, is expressed ubiquitously in the human body, and specifically is abundant in several cancer tissues as mentioned above.…”

Radiation‐induced gene expression profile of human cells deficient in 8‐hydroxy‐2′‐deoxyguanine glycosylase

“…ACE plays a vital role in the metabolism of biologically active peptides and is a pleiotropic hormone, capable of serving as a neurotransmitter, growth factor, angiogenesis factor, vasoconstrictor, prothrombotic agent and cytokine. 49 ACE activity was increased in rat lungs following wholebody irradiation. 50 Expression of dopamine receptor D 3 has been reported in peripheral mononuclear cells after radiation exposure, and it has been suggested that the expression of neurotransmitter receptor is an indicator of neuronal damage after exposure to radiation.…”

Pilot study of angiotensin II receptor blocker in advanced hormone-refractory prostate cancer

“…Surprisingly, it has been reported that quinapril, an angiotensinconverting enzyme inhibitor (ACEI), was useful in a patient with advanced-stage pancreatic cancer. 17 After the patient started quinapril, although her carbohydrate antigen (CA)19 level rose and later dropped, her condition improved dramatically and remained excellent for an additional 12 months. This clinical course is similar to those of our patients with advanced HRPC treated with an ARB.…”