Background-Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabolizing several peptide substrates. We hypothesized that ACE2 is a negative regulator of angiotensin II (Ang II)-mediated signaling and its adverse effects on the cardiovascular system. Methods and Results-Ang II infusion (1.5 mg ⅐ kg Ϫ1 ⅐ d Ϫ1) for 14 days resulted in worsening cardiac fibrosis and pathological hypertrophy in ACE2 knockout (Ace2 Ϫ/y ) mice compared with wild-type (WT) mice. Daily treatment of Ang II-infused wild-type mice with recombinant human ACE2 (rhACE2; 2 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 IP) blunted the hypertrophic response and expression of hypertrophy markers and reduced Ang II-induced superoxide production. Ang II-mediated myocardial fibrosis and expression of procollagen type I␣1, procollagen type III␣1, transforming growth factor-␤1, and fibronectin were also suppressed by rhACE2. Ang II-induced diastolic dysfunction was inhibited by rhACE2 in association with reduced plasma and myocardial Ang II and increased plasma Ang 1-7 levels. rhACE2 treatment inhibited Ang II-mediated activation of protein kinase C-␣ and protein kinase C-␤1 protein levels and phosphorylation of the extracellular signal-regulated 1/2, Janus kinase 2, and signal transducer and activator of transcription 3 signaling pathways in wild-type mice. A subpressor dose of Ang II (0.15 mg ⅐ kg) resulted in a milder phenotype that was strikingly attenuated by rhACE2 (2 mg ⅐ kgIn adult ventricular cardiomyocytes and cardiofibroblasts, Ang II-mediated superoxide generation, collagen production, and extracellular signal-regulated 1/2 signaling were inhibited by rhACE2 in an Ang 1-7-dependent manner. Importantly, rhACE2 partially prevented the development of dilated cardiomyopathy in pressure-overloaded wild-type mice. Conclusions-Elevated Ang II induced hypertension, myocardial hypertrophy, fibrosis, and diastolic dysfunction, which were exacerbated by ACE2 deficiency, whereas rhACE2 attenuated Ang II-and pressure-overload-induced adverse myocardial remodeling. Hence, ACE2 is an important negative regulator of Ang II-induced heart disease and suppresses adverse myocardial remodeling. (Circulation. 2010;122:717-728.)Key Words: angiotensin Ⅲ signal transduction Ⅲ hypertrophy Ⅲ remodeling Ⅲ diastole A ctivation of the renin-angiotensin system (RAS) and the subsequent generation of angiotensin (Ang) II are important mediators of myocardial fibrosis, pathological hypertrophy, and heart failure. 1-3 Pathological hypertrophy and increased myocardial interstitial fibrosis contribute to increased ventricular wall stiffness, thereby impairing cardiac diastolic function, and represent an important risk factor for heart failure in experimental models and patients. 4 -6 Drugs that target Ang II and the Ang II type 1 receptor (AT 1 ) are widely used for the treatment of cardiovascular diseases such as hypertension, myocardial infarction, and heart failure. 7 Angiotensin-converting enzyme 2 (ACE2) is a pleiotropic monocarboxypeptidase capable of metabo...

Background-Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase that metabolizes Ang II into Ang 1-7, thereby functioning as a negative regulator of the renin-angiotensin system. We hypothesized that ACE2 deficiency may compromise the cardiac response to myocardial infarction (MI). Methods and Results-In response to MI (induced by left anterior descending artery ligation), there was a persistent increase in ACE2 protein in the infarct zone in wild-type mice, whereas loss of ACE2 enhanced the susceptibility to MI, with increased mortality, infarct expansion, and adverse ventricular remodeling characterized by ventricular dilation and systolic dysfunction. In ACE2-deficient hearts, elevated myocardial levels of Ang II and decreased levels of Ang 1-7 in the infarct-related zone was associated with increased production of reactive oxygen species. ACE2 deficiency leads to increased matrix metalloproteinase (MMP) 2 and MMP9 levels with MMP2 activation in the infarct and peri-infarct regions, as well as increased gelatinase activity leading to a disrupted extracellular matrix structure after MI. Loss of ACE2 also leads to increased neutrophilic infiltration in the infarct and peri-infarct regions, resulting in upregulation of inflammatory cytokines, interferon-␥, interleukin-6, and the chemokine, monocyte chemoattractant protein-1, as well as increased phosphorylation of ERK1/2 and JNK1/2 signaling pathways. Treatment of Ace2 Ϫ/y -MI mice with irbesartan, an AT1 receptor blocker, reduced nicotinamide-adenine dinucleotide phosphate oxidase activity, infarct size, MMP activation, and myocardial inflammation, ultimately resulting in improved post-MI ventricular function. Conclusions-We conclude that loss of ACE2 facilitates adverse post-MI ventricular remodeling by potentiation of Ang II effects by means of the AT1 receptors, and supplementing ACE2 can be a potential therapy for ischemic heart disease. (Circ Heart Fail. 2009;2:446-455.)

Angiotensin-converting enzyme 2 (ACE2) is a monocarboxypeptidase capable of metabolizing angiotensin (Ang) II into Ang 1 to 7. We hypothesized that ACE2 is a negative regulator of Ang II signaling and its adverse effects on the kidneys. Ang II infusion (1.5 mg/kg⁻¹/d⁻¹) for 4 days resulted in higher renal Ang II levels and increased nicotinamide adenine dinucleotide phosphate oxidase activity in ACE2 knockout (Ace2(-/y)) mice compared to wild-type mice. Expression of proinflammatory cytokines, interleukin-1β and chemokine (C-C motif) ligand 5, were increased in association with greater activation of extracellular-regulated kinase 1/2 and increase of protein kinase C-α levels. These changes were associated with increased expression of fibrosis-associated genes (α-smooth muscle actin, transforming growth factor-β, procollagen type Iα1) and increased protein levels of collagen I with histological evidence of increased tubulointerstitial fibrosis. Ang II-infused wild-type mice were then treated with recombinant human ACE2 (2 mg/kg⁻¹/d⁻¹, intraperitoneal). Daily treatment with recombinant human ACE2 reduced Ang II-induced pressor response and normalized renal Ang II levels and oxidative stress. These changes were associated with a suppression of Ang II-mediated activation of extracellular-regulated kinase 1/2 and protein kinase C pathway and Ang II-mediated renal fibrosis and T-lymphocyte-mediated inflammation. We conclude that loss of ACE2 enhances renal Ang II levels and Ang II-induced renal oxidative stress, resulting in greater renal injury, whereas recombinant human ACE2 prevents Ang II-induced hypertension, renal oxidative stress, and tubulointerstitial fibrosis. ACE2 is an important negative regulator of Ang II-induced renal disease and enhancing ACE2 action may have therapeutic potential for patients with kidney disease.

In the absence of ACE2, biomechanical stress triggers activation of the myocardial NAPDH oxidase system with a critical role of the p47(phox) subunit. Increased production of superoxide, activation of MMP, and pathological signalling leads to severe adverse myocardial remodelling and dysfunction in ACE2KO mice.

Rationale: Mechanotransduction and the response to biomechanical stress is a fundamental response in heart disease. Loss of phosphoinositide 3-kinase (PI3K)␥, the isoform linked to G protein-coupled receptor signaling, results in increased myocardial contractility, but the response to pressure overload is controversial. Objective:To characterize molecular and cellular responses of the PI3K␥ knockout (KO) mice to biomechanical stress. Methods and Results:In response to pressure overload, PI3K␥KO mice deteriorated at an accelerated rate compared with wild-type mice despite increased basal myocardial contractility. These functional responses were associated with compromised phosphorylation of Akt and GSK-3␣. In contrast, isolated single cardiomyocytes from banded PI3K␥KO mice maintained their hypercontractility, suggesting compromised interaction with the extracellular matrix as the primary defect in the banded PI3K␥KO mice. ␤-Adrenergic stimulation increased cAMP levels with increased phosphorylation of CREB, leading to increased expression of cAMP-responsive matrix metalloproteinases (MMPs), MMP2, MT1-MMP, and MMP13 in cardiomyocytes and cardiofibroblasts. Loss of PI3K␥ resulted in increased cAMP levels with increased expression of MMP2, MT1-MMP, and MMP13 and increased MMP2 activation and collagenase activity in response to biomechanical stress. Selective loss of N-cadherin from the adhesion complexes in the PI3K␥KO mice resulted in reduced cell adhesion. The ␤-blocker propranolol prevented the upregulation of MMPs, whereas MMP inhibition prevented the adverse remodeling with both therapies, preventing the functional deterioration in banded PI3K␥KO mice. In banded wild-type mice, long-term propranolol prevented the adverse remodeling and systolic dysfunction with preservation of the N-cadherin levels. Conclusions:The enhanced propensity to develop heart failure in the PI3K␥KO mice is attributable to a cAMP-dependent upregulation of MMP expression and activity and disorganization of the N-cadherin/␤-catenin cell adhesion complex. ␤-Blocker therapy prevents these changes thereby providing a novel mechanism of action for these drugs. (Circ Res. 2010;107:1275-1289.)

Summary:Data were analyzed on 178 consecutive patients (median age 43 years) who underwent autologous blood stem cell transplantation (ABSCT) at a single institution to determine if CD34 + subsets (CD34 + 38 − , CD34 + 33 − , CD34 + 33 + , CD34 + 41 + ) or various clinical factors affect hematopoietic engraftment independent of the total CD34 + cell dose/kg. Using Cox proportional hazards models, the factors independently associated with rapid neutrophil engraftment were higher CD34 + dose/kg, use of G-CSF post-ABSCT, and conditioning regimen (single-agent melphalan ± TBI slower). Factors independently associated with rapid platelet engraftment were higher CD34 + cell dose/kg, higher ratio of CD34 + 33 − /total CD34 + cells infused, conditioning regimen (mitoxantrone, vinblastine, cyclophosphamide faster), and no CD34 + cell selection of the autograft. The CD34 + cell selection process seemed to deplete CD34 + 41 + cells to a greater extent than total CD34 + cells which may explain our observation that it resulted in slower platelet engraftment. In conclusion, the total CD34 + dose/kg was a better predictor of hematopoietic engraftment following ABSCT than the dose of any CD34 + subset. Platelet engraftment, however, was also influenced by the ratio of CD34 + 33 − /total CD34 + cells for unmanipulated autografts, and possibly by the CD34 + 41 + dose for autografts manipulated by CD34 + selection. The use of CD34 + subsets requires further investigation in predicting engraftment of autografts which undergo ex vivo manipulation.

Background: As a product of electronic health, teledermatology is a cost-effective means of improving access to care, facilitating specialist consultations, and supporting patient self-management. Even so, use of traditional teledermatology services is limited by infrastructure and costs in the form of digital cameras, computers, and Internet access.Methods: Considering the significant improvement in smartphone camera resolution and the rapidly increasing number of physicians using smartphones, we explored the use of smartphones as reliable, effective clinical tools in store-and-forward teledermatology. We describe the technical specifications of modern smartphone cameras, the widespread use of smartphones by physicians, and the advantages of smartphones over traditional camera and Internet teledermatology, and we propose recommendations as to how mobile teledermatology may be more effectively used in modern dermatologic practice.Contexte: La té lé dermatologie, en tant que produit é lectronique de santé , est un moyen efficace d'accroître l'accè s aux soins, de faciliter les consultations de spé cialistes et de soutenir les patients dans leur prise en charge personnelle. Toutefois, l'infrastructure né cessaire et les coû ts lié s aux camé ras numé riques, aux ordinateurs et à l'accè s Internet freinent l'utilisation des services en té lé dermatologie classique.Mé thode: Compte tenu de la ré solution grandement amé lioré e des camé ras de té lé phones intelligents et du nombre, en croissance rapide, de mé decins qui font usage de ce type d'appareil, l'é tude a porté sur l'utilisation des té lé phones intelligents comme outil clinique fiable et efficace, doté des fonctions d'enregistrement et de retransmission, en té lé dermatologie. Nous faisons é tat des caracté ristiques techniques des camé ras installé es dans les té lé phones intelligents de derniè re gé né ration, de l'utilisation ré pandue des té lé phones intelligents par les mé decins ainsi que des avantages des té lé phones intelligents comparativement aux camé ras ordinaires et à la té lé dermatologie par Internet; à cela s'ajoutent des recommandations sur la maniè re de rendre plus efficace encore le recours à la té lé dermatologie en mé decine moderne.

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