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Angiotensin-converting enzyme (ACE) is a zinc-dependent peptidase responsible for converting angiotensin I into the vasoconstrictor angiotensin II. However, ACE is a relatively nonspecific peptidase that is capable of cleaving a wide range of substrates. Because of this, ACE and its peptide substrates and products affect many physiologic processes, including blood pressure control, hematopoiesis, reproduction, renal development, renal function, and the immune response. The defining feature of ACE is that it is composed of two homologous and independently catalytic domains, the result of an ancient gene duplication, and ACE-like genes are widely distributed in nature. The two ACE catalytic domains contribute to the wide substrate diversity of ACE and, by extension, the physiologic impact of the enzyme. Several studies suggest that the two catalytic domains have different biologic functions. Recently, the X-ray crystal structure of ACE has elucidated some of the structural differences between the two ACE domains. This is important now that ACE domain-specific inhibitors have been synthesized and characterized. Once widely available, these reagents will undoubtedly be powerful tools for probing the physiologic actions of each ACE domain. In turn, this knowledge should allow clinicians to envision new therapies for diseases not currently treated with ACE inhibitors. more...

Many articles have described the biochemistry of the renin-angiotensin system (RAS). Simply put, renin and angiotensin-converting enzyme (ACE) produce angiotensin II, which affects the brain (increased thirst), the gut (increased salt absorption), the adrenals (aldosterone production), the kidneys (salt and water retention), the heart (increased cardiac output), and vascular smooth muscle (vasoconstriction). Inhibitors of ACE and the angiotensin II type 1 receptor are now widely used to reduce blood pressure and to treat hypertension, heart failure, and renal disease.1 The effectiveness of these drugs and abundant data from animal models show that the RAS is the body's central mechanism for regulating blood pressure. Modern studies of the RAS have substantially broadened the known roles of this system by showing that angiotensin II influences cellular proliferation and the inflammatory response. Although this wider interpretation of the RAS encompasses more than control of blood pressure, it still focuses on the effects of angiotensin II in the context of vascular injury. This increased understanding of the RAS inevitably leads to the question of whether, even now, we fully understand all of the physiological roles of the RAS. Here, we argue that the answer is no, that nature uses the components of the RAS and, in particular, ACE for a wide variety of physiological tasks. ### ACE Is Necessary for Renal Development and Normal Male Fertility In understanding the function of the RAS, a powerful tool is the ability to genetically alter mouse genes. Knockout studies of angiotensinogen, renin, ACE, or the angiotensin II type 1 receptor have confirmed the important role of these proteins in regulating blood pressure, but they also underline the wider physiological role for the RAS.2 For example, adult mice lacking ACE show marked abnormalities of renal development characterized by hypertrophy of small arteries, interstitial fibrosis, atrophy of the inner medulla and renal papilla, and dilation of calyces. Renal … more...

The kidney is an important source of angiotensin-converting enzyme (ACE) in many species, including humans. However, the specific effects of local ACE on renal function and, by extension, BP control are not completely understood. We previously showed that mice lacking renal ACE, are resistant to the hypertension induced by angiotensin II infusion. Here, we examined the responses of these mice to the low-systemic angiotensin II hypertensive model of nitric oxide synthesis inhibition with L-NAME. In contrast to wild-type mice, mice without renal ACE did not develop hypertension, had lower renal angiotensin II levels, and enhanced natriuresis in response to L-NAME. During L-NAME treatment, the absence of renal ACE was associated with blunted GFR responses; greater reductions in abundance of proximal tubule Na+/H+ exchanger 3, Na+/Pi co-transporter 2, phosphorylated Na+/K+/Cl- cotransporter, and phosphorylated Na+/Cl- cotransporter; and greater reductions in abundance and processing of the γ isoform of the epithelial Na+ channel. In summary, the presence of ACE in renal tissue facilitates angiotensin II accumulation, GFR reductions, and changes in the expression levels and post-translational modification of sodium transporters that are obligatory for sodium retention and hypertension in response to nitric oxide synthesis inhibition. Fil: Giani, Jorge Fernando. Cedars Sinai Medical Center; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Janjulia, Tea. Cedars Sinai Medical Center; Estados Unidos Fil: Kamat, Nikhil. University of Southern California; Estados Unidos Fil: Seth, Dale M.. University of Tulane; Estados Unidos Fil: Blackwell, Wendell-Lamar B.. Cedars Sinai Medical Center; Estados Unidos Fil: Shah, Kandarp H.. Cedars Sinai Medical Center; Estados Unidos Fil: Shen, Xiao Z.. Cedars Sinai Medical Center; Estados Unidos Fil: Fuchs, Sebastien. Western University of Health Sciences; Estados Unidos Fil: Delpire, Eric. Vanderbilt University; Estados Unidos Fil: Toblli, Jorge Eduardo. Hospital Aleman; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Bernstein, Kenneth E.. Cedars Sinai Medical Center; Estados Unidos Fil: McDonough, Alicia A.. University of Southern California; Estados Unidos Fil: Gonzalez Villalobos, Romer A.. Cedars Sinai Medical Center; Estados Unidos more...

Rapid progress in genomics and nanotechnology continue to advance our approach to patient care, from diagnosis and prognosis, to targeting and personalization of therapeutics. However, the clinical application of molecular diagnostics in ophthalmology has been limited even though there have been demonstrations of disease risk and pharmacogenetic associations. There is a high clinical need for therapeutic personalization and dosage optimization in ophthalmology and may be the focus of individualized medicine in this specialty. In several retinal conditions, such as age-related macular degeneration, diabetic macular edema, retinal vein occlusion and pre-threshold retinopathy of prematurity, anti-vascular endothelial growth factor therapeutics have resulted in enhanced outcomes. In glaucoma, recent advances in cytoskeletal agents and prostaglandin molecules that affect outflow and remodel the trabecular meshwork have demonstrated improved intraocular pressure control. Application of recent developments in nanoemulsion and polymeric micelle for targeted delivery and drug release are models of dosage optimization, increasing efficacy and improving outcomes in these major eye diseases. more...

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells which accumulate in cancer, infection and chronic inflammation. These cells suppress T cell function and the immune response. Angiotensin converting enzyme (ACE) is a peptidase that is now known to regulate aspects of myelopoiesis. Here, we show that ACE expression correlates with myeloid maturation in vitro. Forced ACE over expression in monocytic cells reduces the generation of MDSCs. In vivo, mice with a genetic change resulting in myeloid cell ACE over-expression have reduced numbers of blood and splenic MDSCs in a tumor model and in a model of chronic inflammation induced by complete Freund’s adjuvant. In contrast, ACE null mice produce large numbers of MDSCs during chronic inflammation. Macrophages from mice with myeloid ACE over-expressing are more pro-inflammatory and have more tumor-killing activity than cells from wild type mice. Thus, manipulating myeloid ACE activity can interfere with MDSCs development and the maturation of myeloid cells. more...

Angiotensin-converting enzyme (ACE) is best known for the catalytic conversion of angiotensin I to angiotensin II. However, the use of gene-targeting techniques has led to mouse models highlighting many other biochemical properties and actions of this enzyme. This review discusses recent studies examining the functional significance of ACE tissue-specific expression and the presence in ACE of two independent catalytic sites with distinct substrates and biological effects. It is these features which explain why ACE makes important contributions to many different physiological processes including renal development, blood pressure control, inflammation, and immunity. more...

Objective: Previously, we showed that inhibition of prolyloligopeptidase eliminated the differences in macrophage TNFα expression and BP response in mice lacking N-domain activity of ACE. Thus, functional studies of BP and inflammatory response in a model lacking prolylendopeptidase activity are performed. Results: After a 14 day high-dose AngII infusion (980 ng/kg-min), POP-KO(n=12) BP was 130±3 mmHg and 147±4 mmHg for POP-WT(n=12). After 14 days of low-dose AngII infusion(490 ng/kg-min), POP-KO(n=8) BP was 126±4 mmHg and 139±3 mmHg for POP-WT(n=8). To investigate differences in the inflammatory response, we examined peritoneal macrophage cytokine expression in response to AngII. The percentage of F4/80+/TNFαhigh cells vs. total F4/80+ was 17%±4.7% for POP-KO (n=8) and 49%±2.8% for POP-WT (n=8)[p Conclusion: Inflammation is an emerging player in hypertension and prolylendopeptidase inhibition may play a role in reducing that inflammation. In the POP-KO mouse model, baseline differences in quantity and quality of inflammatory cells may contribute to the phenotypic differences found in vivo . more...

In the field of oncology, clinical molecular diagnostics and biomarker discoveries are constantly advancing as the intricate molecular mechanisms that transform a normal cell into an aberrant state in concert with the dysregulation of alternative complementary pathways are increasingly understood. Progress in biomarker technology, coupled with the companion clinical diagnostic laboratory tests, continue to advance this field, where individualized and customized treatment appropriate for each individual patient define the standard of care. Here, we discuss the current commonly used predictive pharmacogenetic biomarkers in clinical oncology molecular testing: BRAF V600E for vemurafenib in melanoma; EML4-ALK for crizotinib and EGFR for erlotinib and gefitinib in non-small-cell lung cancer; KRAS against the use of cetuximab and panitumumab in colorectal cancer; ERBB2 (HER2/neu) for trastuzumab in breast cancer; BCR-ABL for tyrosine kinase inhibitors in chronic myeloid leukemia; and PML/RARα for all-trans-retinoic acid and arsenic trioxide treatment for acute promyelocytic leukemia. more...

—Angiotensin-converting enzyme (ACE) is composed of the N- and C-terminal catalytic domains. To study the role of the ACE domains in the inflammatory response, N-knockout (KO) and C-KO mice, models lacking 1 of the 2 ACE domains, were analyzed during angiotensin II–induced hypertension. At 2 weeks, N-KO mice have systolic blood pressures that averaged 173±4.6 mm Hg, which is more than 25 mm Hg higher than the blood pressures observed in wild-type or C-KO mice (146±3.2 and 147±4.2 mm Hg). After 3 weeks, blood pressure differences between N-KO, C-KO, and wild-type were even more pronounced. Macrophages from N-KO mice have increased expression of tumor necrosis factor α after stimulation with either lipopolysaccharide (about 4-fold) or angiotensin II (about 2-fold), as compared with C-KO or wild-type mice. Inhibition of the enzyme prolyl oligopeptidase, responsible for the formation of acetyl-SerAspLysPro and other peptides, eliminated the blood pressure difference and the difference in tumor necrosis factor α expression between angiotensin II–treated N-KO and wild-type mice. However, this appears independent of acetyl-SerAspLysPro. These data establish significant differences in the inflammatory response as a function of ACE N- or C-domain catalytic activity. They also indicate a novel role of prolyl oligopeptidase in the cytokine regulation and in the blood pressure response to experimental hypertension. more...