Reduction Of Angiotensin-converting Enzyme Research Articles

Therapeutic potential of curcumin in ARDS and COVID-19.

Curcumin is a safe, non-toxic, readily available and naturally occurring compound, an active constituent of Curcuma longa (turmeric). Curcumin could potentially treat diseases, but faces poor physicochemical and pharmacological characteristics. To overcome these limitations, we developed a stable, water-soluble formulation of curcumin called cyclodextrin-complexed curcumin (CDC). We have previously shown that direct delivery of CDC to the lung following lipopolysaccharides exposure reduces acute lung injury (ALI) and effectively reduces lung injury, inflammation and mortality in mice following Klebsiella pneumoniae. Recently, we found that administration of CDC led to a significant reduction in angiotensin-converting enzyme 2 and signal transducer and activator of transcription 3 expression in gene and protein levels following pneumonia, indicating its potential in treating coronavirus disease 2019 (COVID-19). In this review, we consider the clinical features of ALI and acute respiratory distress syndrome (ARDS) and the role of curcumin in modulating the pathogenesis of bacterial/viral-induced ARDS and COVID-19.

Testing a Transdermal Nitric Oxide Booster With a Novel Technology to Quantify Total Penile Vascularity and Volume Using Tissue Segmentation Technology Applied to Ultrasound

ABSTRACT Introduction Evaluation of erectile function is challenging. Researchers use validated questionnaires and duplex ultrasound, but these metrics have weaknesses. Morphometrix Imaging Technologies is a unique medical function software Tissue Segmentation Technology (“TST”) applied to ultrasound images. A proprietary mathematical algorithm segments tissue from ultrasound images according to very thin liquid interfaces within the tissue by displaying the interfaces as bright thin lines. The technology quantifies tissue segment counts of ultrasound scanned transverse cross-sections of tissue. Currently this technology is used by veterinarians to evaluate equine ligaments and tendons and under investigation in breast and prostate cancer detection. This study investigated the use of this algorithm on assessing penile vascularity changes after application of a transdermal nitric oxide booster. Objective We sought to determine whether the use of an L-arginine-based transdermal nitric oxide booster would improve penile vascularity if applied every night for 4 weeks. We also evaluated the use of TST versus penile duplex ultrasound as a method to evaluate penile vascularity and cross-sectional area. Methods 14 men between the ages of 48 and 78 (average of 63.) Transdermal medication active ingredient includes L-arginine, Spilanthol, and hops extract. The total formulation is combined with a proprietary and clinically tested delivery technology that creates an electrostatic repulsion while simultaneously increasing potential permeation, retention, and utilization of active compounds. Like iontophoresis, however in a self-contained solution with no external apparatus. The active compounds in the serum work by increasing nitric oxide, vaso-relaxation, activating Matrix GLa protein to reduce vascular stiffness, and reduction of angiotensin converting enzyme. Pre-treatment duplex US measurement of posterior tibial and penile peak systolic and diastolic velocity and post-treatment posterior tibial and penile PSV and PDV. Complete penile ultrasound at 3 cm focal length was recorded before and 10 minutes after application of the serum was sent to Morphometrix for analysis. Subjects applied 2 cc of the serum to the dorsal shaft of the penis every night before bed for 28 days. On the 28th day, a similar pre and post-application ultrasound protocol were applied. Results 50% of patients showed improvement of PSV and tissue segment counts and cross-sectional area at day 28 vs day 0. The other 50% of patients showed minimal change. In general, the patients who did not show improvement (“the non-responders”) had lower baseline tissue segment counts and cross-sectional areas. There was a 72% correlation between the duplex ultrasound PSV measurements and the Morphometrix tissue segment counts. Conclusions We have identified a transdermal L-arginine serum that appears to increase blood flow, cross-sectional area and tissue segment counts in 50% of men. Nocturnal application of this serum would potentially be beneficial in men after non-nerve sparing prostate surgery who no longer get night-time erections. Morphometrix technology can assess penile vascularity in the flaccid state through the use of tissue segment counts. The technology can calculate cross-sectional area and volume. This technology has significant advantages over duplex ultrasound since it provides information about the entire penis and is less operator-dependent. Disclosure Yes, this is sponsored by industry/sponsor: Morphometix Imaging Technologies and OVasc Inc Clarification: No industry support in study design or execution

Abstract 027: Changes in Renin Angiotensin System Monitored Across Time Following Bariatric Surgery

There is scarce information regarding the complete renin-angiotensin-aldosterone system (RAAS) and its changes after bariatric surgery (BS) in patients with morbid obesity (MO). Objective: to analyze changes (Δ) in RAAS components in MO after BS at several follow-up time points. Methods: Fifty-five MO patients (78% women, 40% hypertensives, age 43.4±8.9yr, BMI 42.4±5.3Kg/m 2 ) were evaluated prospectively before and 1,3,6 and 12 months(m) after BS, with assessment of anthropometrics, RAAS components and 24h-systolic BP (SBP). Results: at 12m body weight (-35.1±9.7 Kg) and waist circumference (-27±9.2 cm) decreased (p<0.001). At 1,3 and 6m, there was a reduction in angiotensin-converting enzyme (ACE) and ACE-2 activity, as well as a decrease in plasma renin activity (PRA) and aldosterone from 3m on (Table). The decrease in 24h-SBP at 1m was 6.2 mmHg (3.6 to 8.8), p<0.001. There were correlations (p<0.05) between ΔPRA/Δ24h-SBP at 1m (r=-0.332), 3m (r=-0.330) and 12m (r=-0.322). ΔPRA and Δbody weight correlated only at 1m (r=-0.427). Δaldosterone and Δwaist circumference correlated at 12m (r=-0.372). ΔACE and Δ24h-SBP correlated at 6 and 12m (r=0.451 and r=0.635, respectively). Correlations between Δ24h-SBP and Δbody weight were statistically significant only at 6m (r=0,366; p=0,016). Conclusions: there are sequential changes in several components of the RASS after BS, with an increase in ACE and ACE2 activity as early as 1m after BS that lasts until 6m, and a decrease in PRA and plasma Aldosterone that initiates at 3m and remains 12m after BS. These changes correlate with the decrease of 24h-SBP. RAAS components, but not body weight, appear to correlate with changes in BP after BS.

Knockdown of TFPI-Anchored Endothelial Cells Exacerbates Lipopolysaccharide-Induced Acute Lung Injury Via NF-κB Signaling Pathway.

ABSTRACTAs activation of the coagulation system is both a consequence and contributor to acute lung injury (ALI), pulmonary coagulopathy has become a potential target for therapeutic intervention in ALI patients. We investigated the effects and possible mechanisms of endothelial cell (EC)-anchored tissue factor pathway inhibitor (TFPI) on lipopolysaccharide (LPS)-induced ALI in mice. To assess the effect of EC-anchored TFPI deletion on ALI indices, TFPI knockout (cKO) mice were generated. Mice were instilled by direct intratracheal injection LPS for the preparation of an ALI model. Evans blue dye (EBD) was injected intravenously 2 h prior to animal sacrifice (48 h post-LPS). Lungs were fixed for histopathology and the prepared tissue was homogenized or used to extract bronchoalveolar lavage fluid (BALF) or detect EBD concentration. TFPI knockdown mice with ALI were compared to wild-type (WT) mice with ALI to assess the effect of TFPI on endothelial barrier function and inflammation. TFPI deletion markedly exacerbated LPS histopathological changes in lung, and the LPS changes in protein, EBD extravasation, proinflammatory cytokines TNF-α, IL-1β, and IL-6 in BALF in lung. The number and infiltration of white blood cells (WBCs) from BALF and lung tissue of TFPI cKO mice with LPS-challenged ALI was increased compared to WT mice with LPS-challenged ALI. We also found further increased toll-like receptor 4 and nuclear factor kappa-light-chain-enhancer of activated B cells activation and additional expression of vascular cell adhesion molecule 1 and reduction of angiotensin converting enzyme 2 expression in TFPI cKO+LPS mice compared with WT+LPS mice. Endothelial-specific TFPI deficiency promoted LPS-induced pulmonary inflammation and endothelial barrier permeability possibly via toll-like receptor 4-mediated nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway activation.

The Down-Expression of ACE and IDE Exacerbates Exogenous Amyloid-β Neurotoxicity in CB2R-/- Mice.

Alzheimer's disease (AD) is characterized by neuritic plaques and neurofibrillary tangles. It is reported that enzymatic degradation of amyloid-β (Aβ) plays a pivotal role in Aβ accumulation and type-2 cannabinoid receptor (CB2R) participates in Aβ processing in the brain; however, the underlying mechanisms remain unclear. We determined that Aβ degradation-related proteins are significantly different between CB2R-/- mice and wild-type (WT) mice via proteomic analysis. Moreover, the data demonstrated that the angiotensin converting enzyme (ACE) and insulin-degrading enzyme (IDE) levels are substantially attenuated, and the Aβ level is significantly enhanced in CB2R-/--Aβ1-42 mice compared with that of WT-Aβ1-42 mice. Furthermore, Aβ-mediated synaptic dysfunction, the loss of memory associated proteins, and the suppression of glutamatergic transmission are more severe in CB2R-/--Aβ1-42 mice than that in WT-Aβ1-42 mice. CB2R activation could decrease Aβ1-40 and Aβ1-42 levels and enhance ACE and IDE levels with its selective agonist JWH133; however, AM630 (CB2R antagonist) abrogates all changes induced by JWH133 in N2a cells with AβPP overexpression. Taken together, our study demonstrated that the deletion of CB2R reduces exogenous Aβ degradation and aggravates the toxicity of Aβ via the reduction of ACE and IDE, which suggests that CB2R is involved in the onset of AD and a potential therapeutic target for AD.

Discontinuation/Dose Reduction of Angiotensin-Converting Enzyme Inhibitors/Angiotensin Receptor Blockers during Acute Decompensated Heart Failure in African-American Patients with Reduced Left-Ventricular Ejection Fraction

Objectives: Patients with heart failure (HF) and reduced left-ventricular ejection fraction (LVEF) benefit from angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blocker (ARB) therapy. While dose reduction/discontinuation (r/d) of β-blockers (BB) and furosemide in acute decompensated HF (ADHF) worsen outcomes, data on ACEI/ARB are lacking. Methods: To determine the frequency and reasons for ACEI/ARB therapy r/d in ADHF patients, we studied 174 patients with LVEF <40% on ACEI/ARB and BB therapy upon admission over 1 year. Results: ACEI/ARB doses were r/d in 17.2% because of acute kidney injury (56.7%), hypotension (23.3%), and hyperkalemia (10%). Clinical characteristics were similar between patients with r/d and continued therapy. Admission and discharge creatinine (Cr) levels were higher in the r/d group. On multivariate analysis, admission Cr and admission systolic blood pressures were independent predictors of r/d. Among patients with renal dysfunction cited as the r/d reason, Cr did not significantly rise in 23.5%. The r/d group had a longer length of stay (LOS). Conclusions: ACEI/ARB dose is reduced and/or discontinued in nearly one-fifth of all ADHF admissions, and LOS is longer in the ACEI/ARB r/d group. While impaired renal function is the most frequently cited reason, nearly one-fourth of the patients had stable renal function. ACEI/ARB r/d therapy in the setting of ADHF merits further study.

Secretory products from epicardial adipose tissue from patients with type 2 diabetes impair mitochondrial β-oxidation in cardiomyocytes via activation of the cardiac renin-angiotensin system and induction of miR-208a.

Secretory products from epicardial adipose tissue (EAT) from patients with type 2 diabetes (T2D) impair cardiomyocyte function. These changes associate with alterations in miRNA expression, including the induction of miR-208a. Recent studies suggest that activation of the cardiac-specific renin-angiotensin system (RAS) may affect cardiac energy metabolism via induction of miR-208a. This study investigated whether cardiomyocyte dysfunction induced by conditioned media (CM) from EAT-T2D involves activation of the RAS/miR-208a pathway. Therefore, primary adult rat cardiomyocytes were incubated with CM generated from EAT biopsies from patients with T2D and without T2D (ND). Exposing cardiomyocytes to CM-EAT-T2D reduced sarcomere shortening and increased miR-208a expression versus cells exposed to CM-EAT-ND or control medium. The angiotensin II receptor type 1 (AGTR1) antagonist losartan reversed these effects. Accordingly, incubation with angiotensin II (Ang II) reduced sarcomere shortening, and lowered palmitate-induced mitochondrial respiration and carnitine palmitoyltransferase 1c (CPT1c) expression in cardiomyocytes. Locked-nucleic-acid-mediated inhibition of miR-208a function reversed the detrimental effects induced by Ang II. Interestingly, Ang II levels in CM-EAT-T2D were increased by 2.6-fold after culture with cardiomyocytes. The paracrine activation of the cardiac-specific RAS by CM-EAT-T2D was corroborated by increases in the expression of AGTR1 and renin, as well as a reduction in angiotensin-converting enzyme 2 levels. Collectively, these data show that secretory products from EAT-T2D impair cardiomyocyte contractile function and mitochondrial β-oxidation via activation of the cardiac-specific RAS system and induction of miR-208a, and suggest that alterations in the secretory profile of EAT may contribute to the development of diabetes-related heart disease.

Angiotensin-converting enzyme insertion/deletion polymorphism in patients with acute and chronic pancreatitis

Reduction in angiotensin-converting enzyme (ACE) activity has been shown to attenuate pancreatic stellate cell activation and pancreatic fibrosis and suggested as a potential treatment for chronic pancreatitis. The ACE gene insertion/deletion (I/D) polymorphism in intron 16 accounts for nearly half the variation in serum ACE levels. This study determined the frequency of the I/D polymorphism in patients with acute and chronic pancreatitis. In total, 887 patients (346 with alcoholic, 443 with nonalcoholic, and 98 with acute pancreatitis) were enrolled, and were compared with 1294 healthy controls. Genotyping of the I/D polymorphism was performed by PCR or melting curve analyses. No significant differences were found in the prevalence of the ACE-deletion genotype frequencies when patients with alcoholic (27.5%), nonalcoholic (26.4%), and acute pancreatitis (32.7%) were compared with controls (26.9%). Likewise, allele frequencies of the ACE deletion polymorphism were not significantly different in patients with alcoholic (53.8%), nonalcoholic (50.6%), and acute pancreatitis (54.1%) and controls (52.7%). The I/D polymorphism of the ACE gene was not found to be associated with acute and chronic pancreatitis.

ACE and ACE2: their role to balance the expression of angiotensin II and angiotensin-(1–7)

The discovery of angiotensin-converting enzyme 2 (ACE-2) has revealed a far more complex enzymatic cascade that may influence the renin-angiotensin system within the kidney, specifically the expression of the functional products angiotensin II (Ang II) and Ang-(1-7). The regulation of this critical system involved in blood pressure control must now encompass the integral relationship of ACE and ACE-2 activities.

Renin-aldosterone and angiotensin-converting enzyme during prolonged altitude exposure.

The effect of 7 wk altitude exposure on plasma renin activity (PRA), plasma aldosterone concentration (PAC), and angiotensin-converting enzyme (ACE) activity was studied in 10 male subjects at 4,500 m. There was an initial increase in PRA and a reduction in PAC and ACE. The reduction in ACE was significantly greater in the four subjects who had frequently been exposed to extreme altitudes than in the other six subjects. These changes had returned to control values between 12 and 20 days. Exercise caused a marked elevation of PRA and PAC, but the PAC response to PRA was blunted compared with that at sea level. The ratio PAC/PRA at rest was reduced initially but returned to control values with a similar time course to that of ACE activity. The results are compatible with the hypothesis that ACE activity governs the adrenal response to PRA.

Reduction of Angiotensin-Converting Enzyme in Substantia Nigra in Early-Onset Schizophrenia

Reduction of Angiotensin-Converting Enzyme in Substantia Nigra in Early-Onset Schizophrenia