Bidirectional relation between dipeptidyl peptidase 4 and angiotensin II type I receptor signaling.

Cardiometabolic diseases are often associated with heightened levels of angiotensin II (Ang II), which accounts for the observed oxidative stress, inflammation, and fibrosis. Accumulating evidence indicates a parallel upregulation of dipeptidyl dipeptidase 4 (DPP4) activity in cardiometabolic diseases, with its inhibition shown to mitigate oxidative stress, inflammation, and fibrosis. These findings highlight an overlap between the pathophysiological mechanisms used by Ang II and DPP4. Recent evidence demonstrates that targeted inhibition of DPP4 prevents the rise in Ang II and its associated molecules in experimental models of cardiometabolic diseases. Similarly, inhibitors of the angiotensin I-converting enzyme (ACE) or Ang II type 1 receptor (AT1R) blockers downregulate DPP4 activity, establishing a bidirectional relationship between DPP4 and Ang II. Here, we discuss the current evidence supporting the cross talk between Ang II and DPP4, along with the potential mechanisms promoting this cross regulation. A comprehensive analysis of this bidirectional relationship across tissues will advance our understanding of how DPP4 and Ang II collectively promote the development and progression of cardiometabolic diseases.

20-year follow-up of rheumatic mitral stenosis patients after percutaneous mitral commissurotomy: invasive transmitral gradient differential as a predictor of events.

Percutaneous mitral valve commissurotomy (PMC) is a viable alternative to mitral valve (MV) surgery in the treatment of patients with rheumatic mitral stenosis (RMS). In this single-center retrospective study of consecutive patients with RMS submitted to PMC from 1991 to 2008, we analyzed clinical, echocardiographic, and hemodynamic data and events during follow-up (FUP) until December 2021. Major adverse cardiovascular events (MACE) were a combined endpoint of all-cause death, cardiovascular hospitalization, and MV re-intervention. A total of 124 patients were enrolled: 108 (87.1%) were female, with a mean age at PMC of 46 [standard deviation (SD) 11] years. PMC was successful in 91.1%, with a mean reduction in invasive transmitral pressure gradient (TMPG) of 8 (SD 7) mmHg at PMC time. During the mean FUP of 20 (SD 6) years, 51 (41.1%) patients had MV re-intervention (86.3% surgery and 13.7% redo-PMC), 37 (29.8%) were hospitalized, and 30 (24.2%) died. Approximately 75% of patients remained MACE-free after 10 years, and this percentage decreased to around 40% after 20 years; at this time mark, about 8 in 10 patients were alive. A reduction of <5 mmHg in TMPG at PMC time was associated with a 2.7-fold greater rate of MACE compared to a reduction of ≥5 mmHg, independent of MV regurgitation after PMC and moderate disease of other valves (adjusted hazard ratio 2,7; 95% confidence interval 1.395-5.298, p=0.003). In this cohort with favorable long-term results after PMC, a reduction of <5 mmHg in TMPG at PMC time was associated with MACE during FUP. More studies are needed to validate this independent predictor.

Same-day discharge after elective percutaneous closure of patent foramen ovale.

Percutaneous closure of the patent foramen ovale (PFO) is increasingly performed in specific patients with cryptogenic stroke or clinical evidence of a paradoxical embolism. This study was performed to determine the safety of same-day discharge (SDD) following such procedures. This is a prospective, observational study of patients undergoing elective percutaneous PFO closure in a single tertiary center in Portugal between January 2020 and July 2023. AmplatzerTM devices (St. Jude Medical, St. Paul, MN, USA) and NobblestichTM EL (HeartStitch, Inc., Fountain Valley, CA, USA) were used. After 6 months, the following events were looked at: post-procedural paroxysmal atrial fibrillation, stroke, unplanned cardiac re-hospitalization, urgent cardiac surgery, major vascular complications, pericardial effusions, device embolization, and death. We studied 122 consecutive patients (52% female, 68; 48±12 years old) who had elective percutaneous closure with success and no complications. Forty-nine (40%) had SDD. AmplatzerTM devices were used more frequently in the SDD group, while NobblestichTM EL was more common in the overnight group. During the overnight group's follow-up period, there was one non-cardiovascular death; there were no further events. SDD after elective percutaneous closure of PFO was shown to be a safe and successful patient management method, including NobblestichTM, which we describe for the first time. Our results prove the safety of this same-day discharge strategy. We hypothesize that in the near future, in selected cases, PFO closure might become an ambulatory procedure.

Effects of dipeptidyl peptidase 4 inhibition on the endothelial control of the vascular tone.

Dipeptidyl peptidase 4 (DPP4) is a serine protease known to cleave incretin hormones, which stimulate insulin secretion after food intake, a fact that supported the development of its inhibitors (DPP4i or gliptins) for the treatment of type 2 diabetes mellitus. In addition to their glucose-lowering effects, DPP4i show benefits for the cardiovascular system that could be related, at least in part, to their protective action on vascular endothelium. DPP4i have been associated with the reversal of endothelial dysfunction, an important predictor of cardiovascular events and a hallmark of diseases such as atherosclerosis, diabetes mellitus, hypertension, and heart failure. In animal models of these diseases, DPP4i increase nitric oxide bioavailability and limits oxidative stress, thereby improving the endothelium-dependent relaxation. Similar effects on flow-mediated dilation and attenuation of endothelial dysfunction have also been noted in human studies, suggesting a value for gliptins in the clinical scenario, despite the variability of the results regarding the DPP4i used, treatment duration, and presence of comorbidities. In this mini-review, we discuss the advances in our comprehension of the DPP4i effects on endothelial regulation of vascular tone. Understanding the role of DPP4 and its involvement in the signaling mechanisms leading to endothelial dysfunction will pave the way for a broader use of DPP4i in conditions that endothelial dysfunction is a pivotal pathophysiological player.

Transcatheter systemic atrioventricular valve-in-valve implantation in a congenitally corrected transposition of the great arteries patient.

We present an asymptomatic pregnant patient with congenitally corrected transposition of the great arteries and severe atrioventricular bioprosthesis regurgitation - with increased maternal and fetal risk due to volume overload. She was considered high risk for reintervention and was submitted to an off-label post-partum transcatheter valve-in-valve implantation with a Sapiens 3 valve. The procedure was successful, and she remains asymptomatic 30 months after - and even went through another successful pregnancy.

Closure of a perforated endoscopic submucosal dissection eschar using three over-the-scope clips.

We report the use of three partially overlapping over-the-scope clips to close a perforated ESD eschar. This case illustrates the relevance of prompt acting to ensure ESD safety and reinforces the feasibility of endoscopic treatment for challenging iatrogenic perforations, reducing the need for urgent surgery and its related morbidity and mortality.

Gastric cancer screening: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Gastric cancer (GC) screening is recommended in high-risk populations, although screening methods and intervals vary. In intermediate-risk populations, screening through esophagogastroduodenoscopy (EGD) may be considered depending on local resources. The aim of this study was to compare GC screening methods regarding effect on mortality, diagnostic yield and adherence. METHODS: Systematic review and meta-analysis including studies evaluating population-based GC screening. Search was conducted in three online databases (MEDLINE, Scopus and clinicaltrials.gov), along with manual search. RESULTS: Forty-four studies were included. Studies in upper gastrointestinal series (UGIS) demonstrated that GC screening was associated with significantly lower GC mortality rates (OR 0.63, 95% CI 0.55 - 0.73). Benefits on mortality were also found in EGD and serum pepsinogen (PG) studies. EGD was associated with significantly higher GC (0.55%, 95% CI 0.39 - 0.75%) and early-GC (EGC) detection rates (0.48%, 95% CI 0.34 - 0.65%) when compared to UGIS (GC 0.19%, 95% CI 0.10 - 0.31%; EGC 0.08%, 95% CI 0.04 - 0.13%) and PG (GC 0.10%, 95% CI 0.05 - 0.16%; EGC 0.10%, 95% CI 0.04 - 0.19%). Non-invasive methods tended to higher adherence rates when compared to EGD. Regardless of the screening method, individualized recruitment performed better. DISCUSSION: Screening positively impacted GC mortality rates. EGD was associated with higher diagnostic yield, while UGIS and PG tended to higher adherence rates. Screening uptake was predominantly impacted by recruitment strategies independently of the adopted method.

Piezoelectric Electrospun Fibrous Scaffolds for Bone, Articular Cartilage and Osteochondral Tissue Engineering.

Osteochondral tissue (OCT) related diseases, particularly osteoarthritis, number among the most prevalent in the adult population worldwide. However, no satisfactory clinical treatments have been developed to date to resolve this unmet medical issue. Osteochondral tissue engineering (OCTE) strategies involving the fabrication of OCT-mimicking scaffold structures capable of replacing damaged tissue and promoting its regeneration are currently under development. While the piezoelectric properties of the OCT have been extensively reported in different studies, they keep being neglected in the design of novel OCT scaffolds, which focus primarily on the tissue's structural and mechanical properties. Given the promising potential of piezoelectric electrospun scaffolds capable of both recapitulating the piezoelectric nature of the tissue's fibrous ECM and of providing a platform for electrical and mechanical stimulation to promote the regeneration of damaged OCT, the present review aims to examine the current state of the art of these electroactive smart scaffolds in OCTE strategies. A summary of the piezoelectric properties of the different regions of the OCT and an overview of the main piezoelectric biomaterials applied in OCTE applications are presented. Some recent examples of piezoelectric electrospun scaffolds developed for potentially replacing damaged OCT as well as for the bone or articular cartilage segments of this interfacial tissue are summarized. Finally, the current challenges and future perspectives concerning the use of piezoelectric electrospun scaffolds in OCT regeneration are discussed.

Dynamic Crosstalk between Vascular Smooth Muscle Cells and the Aged Extracellular Matrix.

Vascular aging is accompanied by the fragmentation of elastic fibers and collagen deposition, leading to reduced distensibility and increased vascular stiffness. A rigid artery facilitates elastin to degradation by MMPs, exposing vascular cells to greater mechanical stress and triggering signaling mechanisms that only exacerbate aging, creating a self-sustaining inflammatory environment that also promotes vascular calcification. In this review, we highlight the role of crosstalk between smooth muscle cells and the vascular extracellular matrix (ECM) and how aging promotes smooth muscle cell phenotypes that ultimately lead to mechanical impairment of aging arteries. Understanding the underlying mechanisms and the role of associated changes in ECM during aging may contribute to new approaches to prevent or delay arterial aging and the onset of cardiovascular diseases.

Does urgent balloon-assisted enteroscopy impact rebleeding and short-term mortality in overt obscure gastrointestinal bleeding?

BACKGROUND AND AIMS: The diagnostic yield (DY) and therapeutic yield (TY) of balloon-assisted enteroscopy (BAE) in overt obscure gastrointestinal bleeding (OGIB) is higher in the first 72 h. This study aimed to evaluate if this higher DY and TY after urgent BAE impacted the rebleeding rate, time to rebleed and short-term mortality. METHODS: Retrospective cohort-study, which consecutively included all patients submitted to BAE for overt OGIB, between 2010 and 2019. Patients were distributed in 2 groups: (1) Urgent BAE; (2) Non-urgent BAE. Rebleeding was defined as an Hb drop >2 g/dL, need for transfusional support or presence of melena/hematochezia. RESULTS: Fifty-four patients were included, of which 17 (31.5%) were submitted to BAE in the first 72 h. DY and TY of urgent BAE (DY 88.2%; n = 15; TY 94.1%; n = 16) was higher compared to non-urgent BAE (DY 59.5%; n = 22; TY 45.9%; n = 17) (DY p = .03) (TY p = .001). The rebleeding rate at 1, 2, and 5 years was 32.0%, 34.0%and 37.0%, respectively. Rebleeding was lower after urgent BAE (17.6%; n = 3) compared to non-urgent BAE (45.9%; n = 17) (p = .04). Rebleeding tended to occurr earlier in non-urgent BAE, being at 6-months (32.5%) and 36 months (41.3%) (p = .05). OGIB related 30-day mortality was 5.4% (n = 2) for non-urgent BAE and 0% for urgent BAE (p = .5). CONCLUSION: Urgent BAE might be associated with higher DY and TY with lower rebleeding and trend toward higher rebleeding-free time.

Endoscopic and histologic activity assessment considering disease extent and prediction of treatment failure in ulcerative colitis.

BACKGROUND AND AIMS: DUBLIN score allows evaluation of disease activity and extent in ulcerative colitis (UC). This study aimed to evaluate DUBLIN score as a predictor of therapeutic failure as well as to associate endoscopic and histological activity scores to assess their joint performance. METHODS: Retrospective cohort study, with consecutive inclusion of patients undergoing total colonoscopy with serial biopsies between 2016 and 2019. DUBLIN score (0-9) was calculated as the product of Mayo endoscopic score (MSe 0-3) by disease extent (E1-E3). Histological activity was evaluated through Nancy score (0-4). Activity scores were correlated with biomarkers, treatment failure (therapeutic escalation, hospitalization and/or colectomy) and clinical remission at 6 months (Mayo partial score ≤ 1). RESULTS: One-hundred and seven patients were included. In 38.3% (n = 41) there was evidence of endoscopic activity (MSe ≥ 2) and in 50.5% (n = 54) histological activity (Nancy ≥ 2). MSe and DUBLIN scores showed good correlation (r = 0.943; p < .001) and both were significantly higher in patients with histological activity (p < .001). Therapeutic failure occurred in 25.2% (n = 27). MSe, DUBLIN, and Nancy scores were significantly associated with therapeutic failure (p < .001). The areas under the (AUC) ROC curve were 0.74 (MSe; p < .001), 0.78 (DUBLIN; p < .001) and 0.84 (Nancy; p < .001). Joint evaluation of endoscopic and histological activity by combining DUBLIN and Nancy scores was associated with therapeutic failure with a significantly higher AUC of 0.84 (p < .001) compared to the Dublin score alone (p = .003). CONCLUSION: Mayo and DUBLIN endoscopic scores correlated with each other and with histological activity. The joint evaluation of endoscopic and histological activity allowed to predict with greater accuracy treatment failure.

Prediction of adenoma recurrence after piecemeal endoscopic mucosal resection: interobserver agreement and utilization of the Sydney EMR recurrence tool.

Background and aims: Piecemeal endoscopic mucosal resection (pEMR) allows resection of larger non-invasive colorectal lesions. Adenoma recurrence is an important limitation and occurs in ≤20%. The present study aimed to validate the Sydney EMR recurrence tool (SERT) score as a predictor of both endoscopic and histologic recurrence and evaluate interobserver agreement in adenoma recurrence based on endoscopic scar assessment, among nonexperts in EMR.Methods: Retrospective cohort and cross-sectional study, in which all patients submitted to pEMR in a tertiary care center in Portugal, between 2012 and 2018 were included. SERT-score was calculated for all lesions and compared with the SMSA (size, morphology, site, access) score already validated as a predictor of adenoma recurrence. Image based offline analysis was performed to evaluate adenoma recurrence prediction and assess the interobserver agreement within a heterogeneous group of participants, mostly composed by nonexperts in EMR.Results: There was a moderate positive correlation between the SERT and SMSA scores (p <.001; r = 0.61). SERT-score was significantly associated with endoscopic recurrence (p =.005) and histologic recurrence (p = .015). Endoscopic prediction of recurrence had high coefficient of agreement (k-0.806; p < .001).Conclusion: Histologic recurrence after pEMR can be predicted by SERT score and optical diagnosis of recurrent adenoma has high interobserver agreement between nonexperts in EMR.

Predicting the risk of rebleeding after capsule endoscopy in obscure gastrointestinal bleeding - External validation of the RHEMITT Score.

BACKGROUND AND AIMS: Prediction of rebleeding after small bowel capsule endoscopy (SBCE) in obscure gastrointestinal bleeding (OGIB) is challenging. The recently described RHEMITT score includes 7 variables: chronic kidney disease (CKD); heart failure (HF); P1/P2 lesions (Saurin's classification); major bleeding; incomplete examination; smoking and endoscopic treatment. This tool has been shown to accurately predict the risk of recurrence after a SBCE study. The primary aim of this study was to perform an external validation of the RHEMITT score. METHODS: Retrospective cohort-study, which consecutively included all patients submitted to SBCE (Mirocam®) for OGIB between January 2017 and December 2018. Rebleeding was defined as: (1) a drop in hemoglobin>2g/dL or (2) Melena or hematochezia. The RHEMITT score was calculated and subsequently the accuracy of the score for the prediction of rebleeding was assessed. RESULTS: One-hundred and sixty patients were enrolled. Mean age was 65.8±13.6years and 58.1% (n=93) were female. The mean follow-up time was 20 (SD 9) months. Rebleeding occurred in 14.4% (n=23). Rebleeding at 6, 12, 18 and 24 months was 6.3%, 12.0%, 14.2% and 15.5% respectively. There was a significant association between the RHEMITT score and rebleeding (p <0.001). The area under the (AUC) ROC curve was 0.756 (p<0.001). Rebleeding occurred earlier in intermediate and high-risk patients (RHEMITT score >3) being at 6-months 13.6% and 24 months 28.4% (p<0.01). CONCLUSION: The present study carried out in an external validation cohort confirms the usefulness and accuracy of the RHEMITT score in predicting rebleeding after SBCE.

Refractory tracheoesophageal fistula management with Amplatzer Occluder® placement.

Tracheoesophageal fistulas (TEF) in adults can be managed either surgically or endoscopically, depending on their etiology, size, anatomy and patient comorbidities. A 68-year-old female was admitted to the ER due to dysphagia and a cough. The patient had a medical history of TEF resulting from a tracheostomy and prolonged mechanical ventilation. Previous endoscopic treatment had failed, namely 3-attempts of closure with an over-the-scope clip (OTSC®). The patient refused surgery. After a multidisciplinary discussion (Gastroenterology, Pneumology, Surgery and Interventional-Cardiology), we decided to attempt Amplatzer-Occluder® placement. An 8mm Amplatzer-Occluder® was placed from the tracheal side, with sequential opening of the esophageal and tracheal strands (under endoscopic, bronchofibroscopic and fluoroscopic visualization). Nevertheless, migration of the device occurred 8-weeks later. Percutaneous endoscopic gastrostomy (PEG) was placed and the patient was referred to surgery. When there is extensive fibrosis that is not amendable to the application of clips, atrial septal defect occluder devices can be considered to manage TEF. Nevertheless, there is a need to develop strategies to minimize migration risk.

Gastrointestinal and renal involvement in systemic vasculitis.

Vasculitis can also present with GI or solid organ involvement. IgA and ANCA associated vasculitis are more likely to have GI involvement. A 56-year-old female was admitted to the ER due to nausea, vomiting, epigastric pain and fever. The patient had a medical history of acromegaly and chronic kidney disease of an undetermined etiology, elevated C-reactive protein and renal dysfunction. Abdominal-CT revealed duodenal parietal thickening and pancreatic head edema. On esophagogastroduodenoscopy (EGD), duodenal mucosa had a diffusely nodular aspect with ulcerated areas. The following differential diagnosis were made, infectious enteritis, Whipple disease, infiltrative disorder and GI vasculitis. After discussion between a multidisciplinary team of Gastroenterology and Nephrology, they decided to initiate oral glucocorticoids due to worsening of the renal function, which lead to the resolution of digestive symptoms and renal function stabilization. Myeloperoxidase antineutrophilic-cytoplasmic antibodies (MPO-ANCA) were subsequently positive and histology confirmed duodenal involvement by vasculitis. The patient was asymptomatic after 4-weeks, with endoscopic healing and renal function stabilization. GI involvement limited to the duodenum in the setting of ANCA-MPO vasculitis is a rare condition. Moreover, histopathologic confirmation of vasculitis in endoscopic biopsy samples is exceptional.

Obscure gastrointestinal bleeding in the setting of blue rubber bleb nevus syndrome with extensive small bowel involvement.

Blue rubber bleb nevus syndrome (BRBNS) is a rare disorder characterized by multiple vascular malformations of the gastrointestinal (GI) tract, skin and less frequently in solid organs. An 85-year-old male was admitted to the ER due to melena and was under apixaban anticoagulation. Dorsal hemangiomas were identified on physical examination. On admission, he had hemoglobin levels of 7.6g/dl, esophagogastroduodenoscopy was negative and colonoscopy revealed blood clots in all segments, including the terminal ileum. Capsule endoscopy revealed multiple polypoid vinaceous-colored formations in the proximal jejunum and distally active bleeding resulting in limited mucosal observation. The abdominal-CT was normal. Balloon-assisted enteroscopy (BAE) allowed the identification of multiple hemangioma-like purplish blue lesions in the jejunum and ileum without active bleeding. A diagnosis of BRBNS was made based on clinical, imaging and endoscopic findings. Supportive treatment was decided, considering the extent of the lesions and the comorbidities of the patient. Treatment depends on the site, size and number of lesions. Surgical resection is more suitable for limited or life-threatening lesions. Endoscopic treatment with polidocanol, coagulation, band ligation and endoscopic mucosal resection are also available. Sirolimus has been successfully used. However, tolerability and adverse effects limits its use as a rescue therapy.

Fecal microbiota transplantation in the intestinal decolonization of carbapenamase-producing enterobacteriaceae.

BACKGROUND AND AIMS: fecal microbiota transplantation (FMT) is effective for recurrent Clostridium difficile infection (CDI). Intestinal decolonization of carbapenamase-producing enterobacteriaceae (CPE) can prevent transmission and infection by these agents. The aim of this study was to assess CPE decolonization after FMT. METHODS: this was a case-series study that consecutively included all CPE-carriers that underwent FMT between 2014 and 2019. The indications included refractory/recurrent CDI and CPE-decolonization. RESULTS: out of 21 CPE-carriers, eight were excluded due to incomplete post-FMT testing. CPE decolonization was confirmed in 76.9 % (n = 10). The median decolonization time was 16-weeks (IQR-23) and ranged from two to 53 weeks. CONCLUSION: FMT may be used in the clinical practice for CPE-decolonization as an alternative to combined antibiotic regimens.

The rebleeding rate in patients evaluated for obscure gastrointestinal bleeding after negative small bowel findings by device assisted enteroscopy.

BACKGROUND: data on the long-term outcome of patients with obscure gastrointestinal bleeding (OGIB) with positive small bowel findings in capsule endoscopy but negative small bowel findings in device-assisted enteroscopy are scarce. OBJECTIVE: this study aimed to evaluate the rebleeding rate and time to rebleed in patients with no small bowel findings in enteroscopy, after a positive capsule endoscopy in the setting of OGIB. Baseline predictors for rebleeding were assessed. METHODS: a retrospective double-center study was performed, including patients with OGIB with positive findings by capsule endoscopy and negative small bowel findings by enteroscopy. RESULTS: thirty-five patients were included. Rebleeding occurred in 40 % of patients during a median follow-up of 27 months. Further evaluation in patients with a rebleed was performed in 85.7 %, leading to a final diagnosis in 78.6 %. The rebleeding rate increased progressively over time, from 17.2 % at one month to 54.4 % at four years. Overt bleeding at the time of the first episode was a predictor of rebleeding (p = 0.03) according to the multivariate analysis. This was 50 % at one year compared with 21.8 % in patients with occult bleeding on admission. CONCLUSIONS: in obscure gastrointestinal bleeding, long-term follow-up and further evaluation may be considered after a positive capsule endoscopy. Even if there are no small bowel findings by device-assisted enteroscopy. The rebleeding rate in our study was 40 %, mainly in the presence of an overt bleeding on admission.

Mechanism of the drought tolerance of a transgenic soybean overexpressing the molecular chaperone BiP.

Drought is one of major constraints that limits agricultural productivity. Some factors, including climate changes and acreage expansion, indicates towards the need for developing drought tolerant genotypes. In addition to its protective role against endoplasmic reticulum (ER) stress, we have previously shown that the molecular chaperone binding protein (BiP) is involved in the response to osmotic stress and promotes drought tolerance. Here, we analyzed the proteomic and metabolic profiles of BiP-overexpressing transgenic soybean plants and the corresponding untransformed line under drought conditions by 2DE-MS and GC/MS. The transgenic plant showed lower levels of the abscisic acid and jasmonic acid as compared to untransformed plants both in irrigated and non-irrigated conditions. In contrast, the level of salicylic acid was higher in transgenic lines than in untransformed line, which was consistent with the antagonistic responses mediated by these phytohormones. The transgenic plants displayed a higher abundance of photosynthesis-related proteins, which gave credence to the hypothesis that these transgenic plants could survive under drought conditions due to their genetic modification and altered physiology. The proteins involved in pathways related to respiration, glycolysis and oxidative stress were not signifcantly changed in transgenic plants as compared to untransformed genotype, which indicate a lower metabolic perturbation under drought of the engineered genotype. The transgenic plants may have adopted a mechanism of drought tolerance by accumulating osmotically active solutes in the cell. As evidenced by the metabolic profiles, the accumulation of nine primary amino acids by protein degradation maintained the cellular turgor in the transgenic genotype under drought conditions. Thus, this mechanism of protection may cause the physiological activities including photosynthesis to be active under drought conditions.

Cyclic stretch-induced Crp3 sensitizes vascular smooth muscle cells to apoptosis during vein arterialization remodeling.

Vein graft failure limits the long-term patency of the saphenous vein used as a conduit for coronary artery bypass graft. Early graft adaptation involves some degree of intima hyperplasia to sustain the hemodynamic stress, but the progress to occlusion in some veins remains unclear. We have demonstrated that stretch-induced up-regulation of cysteine and glycine-rich protein 3 (Crp3) in rat jugular vein and human saphenous vein in response to arterialization. Here, we developed a Crp3-KO rat to investigate the role of Crp3 in vascular remodeling. After 28 days jugular vein arterialization, the intima layer was 3-fold thicker in the Crp3-KO that showed comparable smooth muscle cells (SMC) proliferation but an absence of early apoptosis observed in the wild-type rat (WT). We then investigated the role of Crp3 in early integrin-mediated signaling apoptosis in isolated jugular SMC. Interestingly, under basal conditions, ceramide treatment failed to induce apoptosis in both WT and Crp3-KO SMC. Under stretch, Crp3 expression increased in WT SMC and ceramide induced apoptosis. Immunoblotting analysis indicated that ceramide stretch-induced apoptosis in SMC is accompanied by a decrease in the phosphorylation status of both Fak and Akt, leading to an increase in Bax expression and caspase-3 cleavage. In contrast, ceramide failed to decrease Fak and Akt phosphorylation in Crp3-KO SMC and, therefore, there was no downstream induction of Bax expression and effector caspase-3 cleavage. Taken together, we provide evidence that stretch-induced Crp3 modulates vein remodeling in response to arterialization by sensitizing SMC to apoptosis.