Association of lifestyle with valvular heart disease progression and life expectancy among elderly people from different socioeconomic backgrounds.

BACKGROUND: Current cardiovascular prevention strategies are based on studies that seldom include valvular heart disease (VHD). The role of modifiable lifestyle factors on VHD progression and life expectancy among the elderly with different socioeconomic statuses (SES) remains unknown. METHODS: This cohort study included 164,775 UK Biobank participants aged 60 years and older. Lifestyle was determined using a five-factor scoring system covering smoking status, obesity, physical activity, diet, and sleep patterns. Based on this score, participants were then classified into "poor," "moderate," or "ideal" lifestyle groups. SES was classified as high or low based on the Townsend Deprivation Index. The association of lifestyle with major VHD progression was evaluated using a multistate mode. The life table method was employed to determine life expectancy with VHD and without VHD. RESULTS: The UK Biobank documented 5132 incident VHD cases with a mean follow-up of 12.3 years and 1418 deaths following VHD with a mean follow-up of 6.0 years. Compared to those with a poor lifestyle, women and men followed an ideal lifestyle had lower hazard ratios for incident VHD (0.66 with 95% CI, 0.59-0.73 for women and 0.77 with 95% CI, 0.71-0.83 for men) and for post-VHD mortality (0.58 for women, 95% CI 0.46-0.74 and 0.62 for men, 95% CI 0.54-0.73). When lifestyle and SES were combined, the lower risk of incident VHD and mortality were observed among participants with an ideal lifestyle and high SES compared to participants with an unhealthy lifestyle and low SES. There was no significant interaction between lifestyle and SES in their correlation with the incidence and subsequent mortality of VHD. Among low SES populations, 60-year-old women and men with VHD who followed ideal lifestyles lived 4.2 years (95% CI, 3.8-4.7) and 5.1 years (95% CI, 4.5-5.6) longer, respectively, compared to those with poor lifestyles. In contrast, the life expectancy gain for those without VHD was 4.4 years (95% CI, 4.0-4.8) for women and 5.3 years (95% CI, 4.8-5.7) for men when adhering to an ideal lifestyle versus a poor one. CONCLUSIONS: Adopting a healthier lifestyle can significantly slow down the progression from free of VHD to incident VHD and further to death and increase life expectancy for both individuals with and without VHD within diverse socioeconomic elderly populations.

Enhanced Postoperative Pain Management and Mobility Following Arthroscopic Knee Surgery: A Comparative Study of Adductor Canal Block with and without IPACK Block.

BACKGROUND Arthroscopic knee surgery (AKS) is minimally invasive, reducing hospital stay compared to traditional surgery, but postoperative pain remains a significant issue. This study compared the analgesic and functional outcomes following AKS following anesthesia using adductor canal block (ACB) with and without anesthesia using the interspace between the popliteal artery and posterior capsule of the knee (IPACK) block under spinal anesthesia (SA). MATERIAL AND METHODS We randomly allocated 120 patients into 3 groups: IPACK+ACB+SA for Group A (n=40), ACB+SA for Group B (n=40), and SA for Group C (n=40). The outcome was the visual analog scale (VAS) score evaluated at rest and during activity at 3 h, 6 h, 12 h, 24 h, and 48 h postoperatively, the frequency of administration of postoperative rescue analgesic, and the maximal walking distance at 24 h and 48 h postoperatively. RESULTS Compared with Group C, the VAS scores in Group A were significantly lower at 48 h postoperatively (P<0.05). There was a significant difference in the frequency of postoperative rescue analgesia use among the 3 groups (P=0.001). In a subgroup analysis of meniscus shaping under arthroscopy, the resting VAS score in Group A was lower than that in Group B and Group C at 48 h postoperatively (P<0.05). The maximum walking distance of Group A was longer than that of Group B and Group C at 24 h and 48 h postoperatively (P<0.01). CONCLUSIONS The effect of postoperative analgesia in the group receiving IPACK combined with ACB after AKS was obviously superior. In arthroscopic meniscus repair surgery, the duration of analgesia was longer, and the maximum walking distance at 48 h postoperatively was longer.

A novel mouse model of calcific aortic valve stenosis.

BACKGROUND: Calcific aortic valve stenosis (CAVS) is one of the most challenging heart diseases in clinical with rapidly increasing prevalence. However, study of the mechanism and treatment of CAVS is hampered by the lack of suitable, robust and efficient models that develop hemodynamically significant stenosis and typical calcium deposition. Here, we aim to establish a mouse model to mimic the development and features of CAVS. METHODS: The model was established via aortic valve wire injury (AVWI) combined with vitamin D subcutaneous injected in wild type C57/BL6 mice. Serial transthoracic echocardiography was applied to evaluate aortic jet peak velocity and mean gradient. Histopathological specimens were collected and examined in respect of valve thickening, calcium deposition, collagen accumulation, osteogenic differentiation and inflammation. RESULTS: Serial transthoracic echocardiography revealed that aortic jet peak velocity and mean gradient increased from 7 days post model establishment in a time dependent manner and tended to be stable at 28 days. Compared with the sham group, simple AVWI or the vitamin D group, the hybrid model group showed typical pathological features of CAVS, including hemodynamic alterations, increased aortic valve thickening, calcium deposition, collagen accumulation at 28 days. In addition, osteogenic differentiation, fibrosis and inflammation, which play critical roles in the development of CAVS, were observed in the hybrid model. CONCLUSIONS: We established a novel mouse model of CAVS that could be induced efficiently, robustly and economically, and without genetic intervention. It provides a fast track to explore the underlying mechanisms of CAVS and to identify more effective pharmacological targets.

Enhancing aortic valve drug delivery with PAR2-targeting magnetic nano-cargoes for calcification alleviation.

Calcific aortic valve disease is a prevalent cardiovascular disease with no available drugs capable of effectively preventing its progression. Hence, an efficient drug delivery system could serve as a valuable tool in drug screening and potentially enhance therapeutic efficacy. However, due to the rapid blood flow rate associated with aortic valve stenosis and the lack of specific markers, achieving targeted drug delivery for calcific aortic valve disease has proved to be challenging. Here we find that protease-activated-receptor 2 (PAR2) expression is up-regulated on the plasma membrane of osteogenically differentiated valvular interstitial cells. Accordingly, we develop a magnetic nanocarrier functionalized with PAR2-targeting hexapeptide for dual-active targeting drug delivery. We show that the nanocarriers effectively deliver XCT790-an anti-calcification drug-to the calcified aortic valve under extra magnetic field navigation. We demonstrate that the nano-cargoes consequently inhibit the osteogenic differentiation of valvular interstitial cells, and alleviate aortic valve calcification and stenosis in a high-fat diet-fed low-density lipoprotein receptor-deficient (Ldlr-/-) mouse model. This work combining PAR2- and magnetic-targeting presents an effective targeted drug delivery system for treating calcific aortic valve disease in a murine model, promising future clinical translation.

The first clinical data of the SAPIEN 3 aortic valve in the treatment of aortic stenosis in China.

Background: Data on outcomes following transcatheter aortic valve replacement with SAPIEN 3 in China is limited as it was approved by the National Medical Products since 2020. The present study was designed to collect clinical data on the SAPIEN 3 aortic valve in Chinese patients with bicuspid aortic valve and tricuspid aortic valve stenosis. Methods: We analyzed the patient characteristics, procedural features and procedural outcomes of the first 438 patients (223 for bicuspid aortic valve and 215 tricuspid aortic valve) from 21 provinces in 74 sites treated with the SAPIEN 3 valve system for transcatheter aortic valve replacement between September 2020 and May 2022. Results: Procedural mortality was 0.7%. 5 cases during the operation were converted to surgery. Among 438 cases, permanent pacemaker implantation was performed in a total of 12 cases (2.7%). The patient had severe leaflet calcification of the aortic valve, with moderate and severe calcification reaching 39.7% and 35.2% respectively. The size of the implanted valves was predominantly 26 mm and 23 mm, reaching 42.5% and 39.5% respectively. The incidence of moderate or severe perivalvular leak in the postoperative period was 0.5%, with a predominance of 90/10 and 80/20 valve deployment height. There was a significant difference in the deployment height of the valve between bicuspid aortic valve and tricuspid aortic valve, with the bicuspid aortic valve having a more deployment height of 90/10. Annulus size in bicuspid aortic valve group was significantly larger than tricuspid aortic valve group. Valve sizing for oversized, within size, and undersized were different between bicuspid aortic valve and tricuspid aortic valve. Conclusions: Procedural success rates were high, with similar and good results for bicuspid aortic valve and tricuspid aortic valve, low perivalvular leak for both valve types, and low permanent pacemaker implantation rates for both valve types. Annulus size, valve sizing and coronary artery height were significantly different in the BAV and TAV group.

Programing Cell Assembly via Ink-Free, Label-Free Magneto-Archimedes Based Strategy.

Tissue engineering raised a high requirement to control cell distribution in defined materials and structures. In "ink"-based bioprintings, such as 3D printing and photolithography, cells were associated with inks for spatial orientation; the conditions suitable for one ink are hard to apply on other inks, which increases the obstacle in their universalization. The Magneto-Archimedes effect based (Mag-Arch) strategy can modulate cell locomotion directly without impelling inks. In a paramagnetic medium, cells were repelled from high magnetic strength zones due to their innate diamagnetism, which is independent of substrate properties. However, Mag-Arch has not been developed into a powerful bioprinting strategy as its precision, complexity, and throughput are limited by magnetic field distribution. By controlling the paramagnetic reagent concentration in the medium and the gaps between magnets, which decide the cell repelling scope of magnets, we created simultaneously more than a hundred micrometer scale identical assemblies into designed patterns (such as alphabets) with single/multiple cell types. Cell patterning models for cell migration and immune cell adhesion studies were conveniently created by Mag-Arch. As a proof of concept, we patterned a tumor/endothelial coculture model within a covered microfluidic channel to mimic epithelial-mesenchymal transition (EMT) under shear stress in a cancer pathological environment, which gave a potential solution to pattern multiple cell types in a confined space without any premodification. Overall, our Mag-Arch patterning presents an alternative strategy for the biofabrication and biohybrid assembly of cells with biomaterials featured in controlled distribution and organization, which can be broadly employed in tissue engineering, regenerative medicine, and cell biology research.

Human antigen R regulates autophagic flux by stabilizing autophagy-associated mRNA in calcific aortic valve disease.

AIMS: The incidence of calcific aortic valve disease (CAVD) has risen over the last decade and is expected to continue rising; however, pharmacological approaches have proven ineffective. In this study, we evaluated the role and underlying mechanisms of human antigen R (HuR)-mediated post-transcriptional regulation in CAVD. METHODS AND RESULTS: We found that HuR was significantly upregulated in human calcified aortic valves and primary aortic valvular interstitial cells (VICs) following osteogenic stimulation. Subsequent functional studies revealed that HuR silencing ameliorated calcification both in vitro and in vivo. For the first time, we demonstrated that HuR directly interacted with the transcript of phosphatidylinositol-5-phosphate 4-kinase, type II, alpha (PIP4K2A), which mediates phosphatidylinositol signalling, facilitates autophagy, and acts as an mRNA stabilizer. HuR positively modulated PIP4K2A expression at the post-transcriptional level and consequently influenced the AKT/mTOR/ATG13 pathway to regulate autophagy and CAVD progression. CONCLUSION: Our study provides new insights into the post-transcriptional regulatory role of HuR in modulating autophagy-positive factors to regulate the pathogenesis of CAVD. Our findings highlight the potential of HuR as an innovative therapeutic target in CAVD treatment.

FAIM Enhances the Efficacy of Mesenchymal Stem Cell Transplantation by Inhibiting JNK-Induced c-FLIP Ubiquitination and Degradation.

Background: The poor survival rates of transplanted mesenchymal stem cells (MSCs) in harsh microenvironments impair the efficacy of MSCs transplantation in myocardial infarction (MI). Extrinsic apoptosis pathways play an important role in the apoptosis of transplanted MSCs, and Fas apoptosis inhibitory molecule (FAIM) is involved in regulation of the extrinsic apoptosis pathway. Thus, we aimed to explore whether FAIM augmentation protects MSCs against stress-induced apoptosis and thereby improves the therapeutic efficacy of MSCs. Methods: We ligated the left anterior descending coronary artery (LAD) in the mouse heart to generate an MI model and then injected FAIM-overexpressing MSCs (MSCsFAIM) into the peri-infarction area in vivo. Moreover, FAIM-overexpressing MSCs were challenged with oxygen, serum, and glucose deprivation (OGD) in vitro, which mimicked the harsh microenvironment that occurs in cardiac infarction. Results: FAIM was markedly downregulated under OGD conditions, and FAIM overexpression protected MSCs against OGD-induced apoptosis. MSCsFAIM transplantation improved cell retention, strengthened angiogenesis, and ameliorated heart function. The antiapoptotic effect of FAIM was mediated by cellular-FLICE inhibitory protein (c-FLIP), and FAIM augmentation improved the protein expression of c-FLIP by reducing ubiquitin-proteasome-dependent c-FLIP degradation. Furthermore, FAIM inhibited the activation of JNK, and treatment with the JNK inhibitor SP600125 abrogated the reduction in c-FLIP protein expression caused by FAIM silencing. Conclusions: Overall, these results indicated that FAIM curbed the JNK-mediated, ubiquitination-proteasome-dependent degradation of c-FLIP, thereby improving the survival of transplanted MSCs and enhancing their efficacy in MI. This study may provide a novel approach to strengthen the therapeutic effect of MSC-based therapy.

Characterization and necrosis-inducing activity of necrosis- and ethylene-inducing peptide 1-like proteins from Colletotrichum australisinense, the causative agent of rubber tree anthracnose.

Colletotrichum australisinense, a member of the Colletotrichum acutatum species complex, is an important pathogen causing rubber tree anthracnose. Genome-wide comparative analysis showed this species complex contains more genes encoding necrosis- and ethylene-inducing peptide 1-like proteins (NLPs) than other Colletotrichum species complexes, but little is known about their necrosis-inducing roles in host. The aim of this study was to analyze NLPs number and type in C. australisinense, and characterize their necrosis-inducing activity in host or non-host. According to phylogenetic relationship, conserved the cysteine residues and the heptapeptide motif (GHRHDWE), 11 NLPs were identified and classified into three types. Five of the eleven NLPs were evaluated for necrosis-inducing activity. CaNLP4 (type 1) could not induce necrosis in host or non-host plants. By contrast, both CaNLP5 and CaNLP9 (type 1) induced necrosis in host and non-host plants, and necrosis-inducing activity was strongest for CaNLP9. CaNLP10 (type 2) and CaNLP11 (type 3) induced necrosis in host but not non-host plants. Substitution of key amino acid residues essential for necrosis induction activity led to loss of CaNLP4 activity. Structural characterization of CaNLP5 and CaNLP9 may explain differences in necrosis-inducing activity. We evaluated the expression of genes coding CaNLP by reverse transcription polymerase chain reaction (RT-PCR) and quantitative real-time PCR (qRT-PCR) at different time-points after pathogen infection. It was found that genes encoding CaNLPs with different activities exhibited significantly different expression patterns. The results demonstrate that CaNLPs are functionally and spatially distinct, and may play different but important roles in C. australisinense pathogenesis.

Transcatheter mitral valve repair in patient with atrial functional mitral regurgitation using novel DragonFly™ device.

We report the first case of transcatheter mitral valve repair with the novel DragonFly™ device, a transcatheter edge-to-edge mitral regurgitation (MR) repair device, in a patient with severe, symptomatic MR due to annular dilation from atrial functional disease (Carpentier type I). The patient had experienced multiple heart failure events and was unsuitable for surgery due to pulmonary dysfunction and obesity.

True cost of surgical aortic valve replacement and implications for price setting and diagnosis-related groups: evidence from a tertiary hospital in Eastern China.

Background: Surgical aortic valve replacement (SAVR) has long been the standard treatment for patients with severe aortic stenosis in China, but the costs of SAVR from a hospital perspective in China have not been thoroughly researched. Currently, diagnosis-related groups in China are based on historical expenses that are closely related to the unit charges set by the official pricing department and are frequently inaccurate compared with actual resource consumption. Materials & methods: Through a retrospective empirical study on the costs and charges of SAVR cases in a tertiary hospital, this study aimed to compare the costs and charges of service items. We collected clinical information from patients undergoing SAVR (isolated or concomitant procedures) and financial information from the hospital in 2015 and 2016. Top-down full cost accounting and step-allocation were the main methods used in this study. Result: This research selected 203 SAVR cases in 2015 and 214 cases in 2016. The median length of hospital stay was 15.92 days (6.07 days pre surgery and 9.57 days post surgery). The average human resource cost of care per day per bed in the cardiovascular surgery department, including doctors and nurses, was US $62.22 in 2015 and $66.17 in 2016, but the corresponding charge was no more than $24. For operation, the cost of isolated SAVR was $665 in 2015 and $1015 in 2016, while the charge was $820. For anesthesiology, the cost of isolated SAVR was $400 in 2015 and $526 in 2016, while the average charge was $192. For examination service items, some costs did not exceed charges. The average total cost of a case was $19,299 ± 8954, while the average total charge was $18,923 ± 9194. Conclusion: SAVR is associated with significant resource utilization and hospital stay duration. The fees for human resources and services associated with SAVR do not reflect the true costs of SAVR in a Chinese hospital setting. This study may assist in future budget planning and price setting for policy makers in China.

SRT1720 Pretreatment Promotes Mitochondrial Biogenesis of Aged Human Mesenchymal Stem Cells and Improves Their Engraftment in Postinfarct Nonhuman Primate Hearts.

Declined function of aged mesenchymal stem cells (MSCs) diminishes the benefits of cell therapy for myocardial infarction (MI). Our previous study has demonstrated that SRT1720, a specific SIRT1 activator, could protect aged human MSCs (hMSCs) against apoptosis. The purpose of the present study was to investigate the role of mitochondria in the antiapoptotic effects of SRT1720. In addition, we established a nonhuman primate MI model to evaluate cell engraftment of SRT1720-pretreated aged hMSCs (SRT1720-OMSCs). A hydrogen peroxide (H2O2)-induced apoptosis model was established in vitro to mimic MI microenvironment. Compared with vehicle-treated aged hMSCs (Vehicle-OMSCs), SRT1720-OMSCs showed alleviated apoptosis level, significantly decreased caspase-3 and caspase-9 activation, and reduced release of cytochrome c when subjected to H2O2 treatment. Mitochondrial contents were compared between young and aged hMSCs and our data showed that aged hMSCs had lower mitochondrial DNA (mtDNA) copy numbers and protein expression levels of components of the mitochondrial electron transport chain (ETC) than young hMSCs. Also, treatment with SRT1720 resulted in enhanced MitoTracker staining, increased mtDNA levels and expression of mitochondrial ETC components in aged hMSCs. Furthermore, SRT1720-OMSCs exhibited elevated mitochondrial respiratory capacity and higher mitochondrial membrane potential. In vivo study demonstrated that SRT1720-OMSCs had higher engraftment rates than Vehicle-OMSCs at 3 days after transplantation into the infarcted nonhuman primate hearts. Taken together, these results suggest that SRT1720 promotes mitochondrial biogenesis and function of aged hMSCs, which is involved in its protective effects against H2O2-induced apoptosis. These findings encourage further exploration of the optimization of aged stem cells function via regulating mitochondrial function.

Aldo-keto reductase family 1 member B induces aortic valve calcification by activating hippo signaling in valvular interstitial cells.

AIMS: Calcific aortic valve disease (CAVD) is a primary cause of cardiovascular mortality; however, its mechanisms are unknown. Currently, no effective pharmacotherapy is available for CAVD. Aldo-keto reductase family 1 member B (Akr1B1) has been identified as a potential therapeutic target for valve interstitial cell calcification. Herein, we hypothesized that inhibition of Akr1B1 can attenuate aortic valve calcification. METHODS AND RESULTS: Normal and degenerative tricuspid calcific valves from human samples were analyzed by immunoblotting and immunohistochemistry. The results showed significant upregulation of Akr1B1 in CAVD leaflets. Akr1B1 inhibition attenuated calcification of aortic valve interstitial cells in osteogenic medium. In contrast, overexpression of Akr1B1 aggravated calcification in osteogenic medium. Mechanistically, using RNA sequencing (RNAseq), we revealed that Hippo-YAP signaling functions downstream of Akr1B1. Furthermore, we established that the protein level of the Hippo-YAP signaling effector active-YAP had a positive correlation with Akr1B1. Suppression of YAP reversed Akr1B1 overexpression-induced Runx2 upregulation. Moreover, YAP activated the Runx2 promoter through TEAD1 in a manner mediated by ChIP and luciferase reporter systems. Animal experiments showed that the Akr1B1 inhibitor epalrestat attenuated aortic valve calcification induced by a Western diet in LDLR-/- mice. CONCLUSION: This study demonstrates that inhibition of Akr1B1 can attenuate the degree of calcification both in vitro and in vivo. The Akr1B1 inhibitor epalrestat may be a potential treatment option for CAVD.

Knockdown of estrogen-related receptor α inhibits valve interstitial cell calcification in vitro by regulating heme oxygenase 1.

Calcific aortic valve disease (CAVD) is the most common valvular heart disease in adults. The cellular mechanisms of CAVD are still unknown, but accumulating evidence has revealed that osteogenic differentiation of human valve interstitial cells (hVICs) plays an important role in CAVD. Thus, we aimed to investigate the function of estrogen-related receptor α (ERRα) in the osteogenic differentiation of hVICs. We found that the level of ERRα was significantly increased in CAVD samples compared to normal controls. In addition, ERRα was significantly upregulated during hVIC osteogenic differentiation in vitro. Gain- and loss-of-function experiments were performed to identify the function of ERRα in hVIC calcification in vitro. Inhibition of endogenous ERRα attenuated hVIC calcification, whereas overexpression of ERRα in hVICs promoted this process. RNA sequencing results suggested that heme oxygenase-1 (Hmox1) was a downstream target of ERRα, which was further confirmed by western blotting. Additionally, we also found that downregulation of Hmox1 by shHmox1 efficiently reversed the inhibition of calcification induced by ERRα shRNA in hVICs. ChIP-qPCR and luciferase assays indicated that Hmox1 was negatively regulated by ERRα. We found that overexpression of Hmox1 or its substrates significantly inhibited hVIC calcification in vitro. In conclusion, we found that knockdown of ERRα can inhibit hVIC calcification through upregulating Hmox1 and that ERRα and Hmox1 are potential targets for the treatment of CAVD.

TPP1 Enhances the Therapeutic Effects of Transplanted Aged Mesenchymal Stem Cells in Infarcted Hearts via the MRE11/AKT Pathway.

BACKGROUND: Poor cell survival after transplantation restricts the therapeutic potential of mesenchymal stem cell (MSC) transplantation into infarcted hearts, particularly in older individuals. TPP1, a component of the shelterin complex that is involved in telomere protection, is highly expressed in young MSCs but declines in aged ones. Here, we explore whether TPP1 overexpression in aged mouse MSCs improves cell viability in vivo and in vitro. METHODS: Aged mouse MSCs overexpressing TPP1 were injected into the peri-infarct area of the mouse heart after left anterior descending coronary artery ligation. In parallel, to evaluate cellular-level effects, H2O2 was applied to MSCs in vitro to mimic the microenvironment of myocardial injury. RESULTS: In vivo, the transplantation of aged MSCs overexpressing TPP1 resulted in improved cell survival, enhanced cardiac function, and reduced fibrosis compared to unmodified aged MSCs. In vitro, TPP1 overexpression protected aged MSCs from H2O2-induced apoptosis and enhanced DNA double-strand break (DSB) repair. In addition, the phosphorylation of AKT and the key DSB repair protein MRE11 were both significantly upregulated in aged MSCs that overexpressed TPP1. CONCLUSIONS: Our results reveal that TPP1 can enhance DNA repair through the AKT/MRE11 pathway, thereby improving the therapeutic effects of aged MSC transplantation and offering significant potential for the clinical application of autologous transplantation in aged patients.

Leptin increases mitochondrial OPA1 via GSK3-mediated OMA1 ubiquitination to enhance therapeutic effects of mesenchymal stem cell transplantation.

Accumulating evidence revealed that mesenchymal stem cells (MSCs) confer cardioprotection against myocardial infarction (MI). However, the poor survival and engraftment rate of the transplanted cells limited their therapeutic efficacy in the heart. The enhanced leptin production associated with hypoxia preconditioning contributed to the improved MSCs survival. Mitochondrial integrity determines the cellular fate. Thus, we aimed to investigate whether leptin can enhance mitochondrial integrity of human MSCs (hMSCs) to protect against various stress. In vivo, transplantation of leptin-overexpressing hMSCs into the infarcted heart resulted in improved cell viability, leading to enhanced angiogenesis and cardiac function. In vitro, pretreatment of hMSCs with recombinant leptin (hMSCs-Leppre) displayed improved cell survival against severe ischemic condition (glucose and serum deprivation under hypoxia), which was associated with increased mitochondrial fusion. Subsequently, Optic atrophy 1 (OPA1), a mitochondrial inner membrane protein that regulates fusion and cristae structure, was significantly elevated in the hMSCs-Leppre group, and the protection of leptin was abrogated by targeting OPA1 with a selective siRNA. Furthermore, OMA1, a mitochondrial protease that cleaves OPA1, decreased in a leptin-dependent manner. Pretreatment of cells with an inhibitor of the proteasome (MG132), prevented leptin-induced OMA1 degradation, implicating the ubiquitination/proteasome system as a part of the protective leptin pathway. In addition, GSK3 inhibitor (SB216763) was also involved in the degradation of OMA1. In conclusion, in the hostile microenvironment caused by MI, (a) leptin can maintain the mitochondrial integrity and prolong the survival of hMSCs; (b) leptin-mediated mitochondrial integrity requires phosphorylation of GSK3 as a prerequisite for ubiquitination-depended degradation of OMA1 and attenuation of long-OPA1 cleavage. Thus, leptin targeting the GSK3/OMA1/OPA1 signaling pathway can optimize hMSCs therapy for cardiovascular diseases such as MI.

Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists.

RATIONALE: Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. To date no treatment strategies have been developed to regulate clinical VC. OBJECTIVE: The objective of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model. METHODS AND RESULTS: Young adult osteoprotegerin-deficient mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409-treated mice were paralleled by markedly lower alkaline phosphatase activity and a dramatic reduction in the expression of transcription factors, including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH-A was dissected in smooth muscle cells isolated from human and mouse aortas. Calcification of smooth muscle cells induced by osteogenic medium was inhibited in the presence of GHRH or MR409, as evidenced by reduced alkaline phosphatase activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor-selective small interfering RNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A which in turn blocked nicotinamide adenine dinucleotide phosphate oxidase activity and reduced production of reactive oxygen species, thus blocking the phosphorylation of nuclear factor κB (p65), a key intermediate in the ligand of receptor activator for nuclear factor-κ B-Runx2/alkaline phosphatase osteogenesis program. A protein kinase A-selective small interfering RNA or the chemical inhibitor H89 abolished these beneficial effects of MR409. CONCLUSIONS: GHRH-A controls osteogenesis in smooth muscle cells by targeting cross talk between protein kinase A and nuclear factor κB (p65) and through the suppression of reactive oxygen species production that induces the Runx2 gene and alkaline phosphatase. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC.

Bispectral index-guided sedation in transfemoral transcatheter aortic valve implantation: a retrospective control study.

OBJECTIVE: Transcatheter aortic valve implantation (TAVI) is a minimally invasive therapy for elderly patients with severe aortic valve stenosis who were refused surgical aortic valve replacement because of the high perioperative risk. Traditionally, this procedure has been done under general anesthesia, but more recently local anesthesia and sedation have become popular. This research assessed the effectiveness of transfemoral TAVI under bispectral index (BIS)-guided sedation. METHODS: In this single-center retrospective control analysis, clinical data, including demographic characteristics, echocardiography, periprocedural data, and main complications, were collected and assessed in 113 patients undergoing TAVI through the femoral artery under general anesthesia (GA group, n=36) and under BIS-guided sedation (SED group, n=77). RESULTS: The demographic characteristics and echocardiographic parameters between the two groups were similar (P>0.05). Two (2.6%) of patients were moved from BIS-guided sedation to general anesthesia for surgical reasons. Procedures were significantly shorter in the SED group than in the GA group ((127.10±44.43) min vs. (165.90±71.62) min, P=0.004). Patients in the SED group lost less blood and received significantly fewer red blood cells and catecholamines than those in the GA group (5.19% vs. 22.22%, P=0.017 and 67.53% vs. 97.22%, P<0.001). The length of hospital stay was significantly shorter and there were fewer pulmonary complications in the SED group than in the GA group. Thirty-day mortality was similar between the two groups. CONCLUSIONS: BIS-guided sedation is a feasible and safe approach for transfemoral TAVI. The anesthesiologist should choose the best anesthetic method according to the team's experience.

SRT1720 promotes survival of aged human mesenchymal stem cells via FAIM: a pharmacological strategy to improve stem cell-based therapy for rat myocardial infarction.

SIRT1 has been proved to rejuvenate and improve the therapeutic efficacy of aged rat mesenchymal stem cells (MSCs). Herein, we investigate the protective effect of pretreatment with SIRT1 activator SRT1720 on aged human MSCs (hMSCs). The optimized pretreatment condition for aged hMSCs was determined to be 0.5 µM SRT1720 for 24 h by monitoring the survival of aged hMSCs subjected to serum deprivation±hypoxia and±500 µM hydrogen peroxide (H2O2). Pretreatment with these conditions increased the survival of aged hMSCs 1 day (2.7-fold) and 3 days (1.9-fold) after being transplanted into a rat myocardial infarction (MI) model created by ligation of the left anterior descending (LAD) coronary artery. Transplantation with SRT1720 pretreated aged hMSCs achieved increased left ventricular ejection fraction (58.9±3.6 versus 52.8±5%) and angiogenesis with reduced fibrosis of rat hearts as compared to DMSO pretreated group 28 days following MI. Unbiased transcriptome analysis conducted on aged hMSCs under oxidative stress indicated the Fas apoptosis inhibitory molecule (FAIM) was significantly upregulated following SRT1720 pretreatment (14.9±0.2-folds). Moreover, the anti-apoptotic effect of SRT1720 was mitigated by FAIM knockdown with a small interfering RNA-targeted FAIM. These results indicated that pretreatment with SRT1720 improves survival of aged hMSCs, and enhances their therapeutic efficacy for rat myocardial infarction (MI). Upregulation of FAIM possibly involves in the mechanisms of the protective effects.

Nicotine Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice by Activating α7 Nicotinic Acetylcholine Receptor on Mast Cells.

OBJECTIVE: Cigarette smoking is an independent risk factor for atherosclerosis. Nicotine, the addictive component of cigarettes, induces mast cell (MC) release and contributes to atherogenesis. The purpose of this study was to determine whether nicotine accelerates atherosclerosis through MC-mediated mechanisms and whether MC stabilizer prevents this pathological process. APPROACH AND RESULTS: Nicotine administration increased the size of atherosclerotic lesions in apolipoprotein E-deficient (Apoe-/-) mice fed a fat-enriched diet. This was accompanied by enhanced intraplaque macrophage content and lipid deposition but reduced collagen and smooth muscle cell contents. MC deficiency in Apoe-/- mice (Apoe-/-KitW-sh/W-sh) diminished nicotine-induced atherosclerosis. Nicotine activated bone marrow-derived MCs in vitro, which was inhibited by a MC stabilizer disodium cromoglycate or a nonselective nicotinic acetylcholine receptor blocker mecamylamine. Further investigation revealed that α7 nicotinic acetylcholine receptor was a target for nicotine activation in MCs. Nicotine did not change atherosclerotic lesion size of Apoe-/-KitW-sh/W-sh mice reconstituted with MCs from Apoe-/-α7nAChR-/- animals. CONCLUSIONS: Activation of α7 nicotinic acetylcholine receptor on MCs is a mechanism by which nicotine enhances atherosclerosis.