Acute oxygen-sensing mechanisms.
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Angiotensin II↗
Biomedical subjects
David W Moskowitz
Publications and source records attributed to David W Moskowitz.
The central role of angiotensin I-converting enzyme in vertebrate pathophysiology.
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.
Adult↗
Is angiotensin I-converting enzyme a "master" disease gene?
Clustering of diseases has been appreciated by health insurers and epidemiologists for some time. Co-morbidity suggests shared pathways of disease. It is by now well agreed that common diseases have a strong genetic component. Here we present evidence that the angiotensin I-converting enzyme (ACE) deletion/deletion (D/D) genotype is associated with a large number of common adult diseases, including cardiovascular disease, cancer, and psychiatric disease. Since the ACE D/D genotype has been shown to be associated with increased levels of tissue ACE expression at the protein level, these data suggest that overactivity of ACE may be involved in the pathogenesis of common diseases, as well as the utility of effective ACE inhibition in their treatment and, perhaps, prevention.
Adult↗
Is "somatic" angiotensin I-converting enzyme a mechanosensor?
"Somatic" angiotensin I-converting enzyme (ACE) appears to be one of the evolutionary advances that made a closed circulation possible, and may have contributed to the Cambrian "explosion" of species approximately 540 million years ago. It also appears to be at the origin of a large number of common human diseases. A model is proposed in which the duplicated form of ACE ("somatic" ACE) functions as a mechanotransducer, defending downstream vessels and tissues from an increase in pressure. In the model, ACE senses shear stress (blood velocity) in regions of turbulent blood flow. An increase in shear stress strips an autoinhibitor tripeptide, FQP, from the N-terminal active site, thereby activating it. The C-terminal domain is constitutively activated by chloride. This model explains the clinical superiority of hydrophobic ACE inhibitors relative to hydrophilic ones.
Animals↗
From pharmacogenomics to improved patient outcomes: angiotensin I-converting enzyme as an example.
Here we report the utility of a molecular epidemiologic approach for common, polygenic diseases. Since 1992, the angiotensin I-converting enzyme (ACE) deletion/deletion (D/D) genotype has been linked to several cardiovascular diseases, including diabetic nephropathy. Earlier, the ACE D/D genotype had been associated with excess tissue ACE activity. We have observed an association of the ACE D/D genotype with a large number of common diseases, including chronic renal failure due to non-insulin-dependent diabetes mellitus or hypertension, hypertensive peripheral vascular disease, and emphysema [chronic obstructive pulmonary disease (COPD)]. ACE inhibitors have been in clinical use since 1977 and have a well-known safety record. Armed with the knowledge that ACE overactivity was associated with their disease, we gave what was intended to be a tissue ACE-inhibitory dose of a hydrophobic ACE inhibitor to 800 Caucasian and African-American male patients with hypertension and 200 Caucasian and African-American male patients with chronic renal failure, over a period of 3 years. We here report their outcomes, which include those of two patients with end-stage hypertensive peripheral vascular disease and one patient with end-stage emphysema (COPD). As a group, the outcomes are superior to what is available in the literature. This experience suggests the power of pharmacogenomics to improve clinical outcomes for common diseases safely, quickly, and inexpensively, if effective drugs already exist.
Angiotensin-Converting Enzyme Inhibitors↗