Prevent Atherosclerosis Progression Research Articles

Enhancement of high-density lipoprotein-associated protease inhibitor activity prevents atherosclerosis progression

Background and aimsInflammatory cells within atherosclerotic lesions secrete proteolytic enzymes that contribute to lesion progression and destabilization, increasing the risk for an acute cardiovascular event. Elastase is a serine protease, secreted by macrophages and neutrophils, that may contribute to the development of unstable plaque. We previously reported interaction of endogenous protease-inhibitor proteins with high-density lipoprotein (HDL), including alpha-1-antitrypsin, an inhibitor of elastase. These findings support a potential role for HDL as a modulator of protease activity. In this study, we test the hypothesis that enhancement of HDL-associated elastase inhibitor activity is protective against atherosclerotic lesion progression. MethodsWe designed an HDL-targeting protease inhibitor (HTPI) that binds to HDL and confers elastase inhibitor activity. Lipoprotein binding and the impact of HTPI on atherosclerosis was examined using mouse models. Histology and immunofluorescence staining of aortic root sections were used to examine the impact of HTPI on lesion morphology and inflammatory features. ResultsHTPI is a small (1.6 kDa) peptide with an elastase inhibitor domain, a soluble linker, and an HDL-targeting domain. When incubated with human plasma ex vivo, HTPI predominantly binds to HDL. Intravenous administration of HTPI to mice resulted in its binding to plasma HDL and increased elastase inhibitor activity on isolated HDL. Accumulation of HTPI within plaque was observed after administration to Apoe-/- mice. To examine the effect of HTPI treatment on atherosclerosis, prevention and progression studies were performed using Ldlr-/- mice fed Western diet. In both study designs, HTPI-treated mice had reduced lipid deposition in plaque. ConclusionsThese data support the hypothesis that HDL-associated anti-elastase activity can improve the atheroprotective potential of HDL and highlight the potential utility of HDL enrichment with anti-protease activity as an approach for stabilization of atherosclerotic lesions.

Protocatechuic aldehyde increases pericyte coverage and mitigates pericyte damage to enhance the atherosclerotic plaque stability

Pericyte dysfunction and loss contribute substantially to the destabilization and rupture of atherosclerotic plaques. Protocatechuic aldehyde (PCAD), a natural polyphenol, exerts anti-atherosclerotic effects. However, the effects and mechanisms of this polyphenol on pericyte recruitment, coverage, and pericyte function remain unknown. We here treated apolipoprotein E-deficient mice having high-fat diet-induced atherosclerosis with PCAD. PCAD achieved therapeutic effects similar to rosuvastatin in lowering lipid levels and thus preventing atherosclerosis progression. With PCAD administration, plaque phenotype exhibited higher stability with markedly reduced lesion vulnerability, which is characterized by reduced lipid content and macrophage accumulation, and a consequent increase in collagen deposition. PCAD therapy increased pericyte coverage in the plaques, reduced VEGF-A production, and inhibited intraplaque neovascularization. PCAD promoted pericyte proliferation, adhesion, and migration to mitigate ox-LDL-induced pericyte dysfunction, which thus maintained the capillary network structure and stability. Furthermore, TGFBR1 silencing partially reversed the protective effect exerted by PCAD on human microvascular pericytes. PCAD increased pericyte coverage and impeded ox-LDL-induced damages through TGF-β1/TGFBR1/Smad2/3 signaling. All these novel findings indicated that PCAD increases pericyte coverage and alleviates pericyte damage to improve the stability of atherosclerotic plaques, which is accomplished by regulating TGF-β1/TGFBR1/Smad2/3 signaling in pericytes.

Whole-Grain Highland Barley Attenuates Atherosclerosis Associated with NLRP3 Inflammasome Pathway and Gut Microbiota in ApoE-/- Mice.

The efficacy and mechanism of highland barley in the treatment of atherosclerosis have received little attention. Herein, we aimed to explore whether highland barley supplementation can prevent atherosclerosis progression and improve gut microbiota disorder in apolipoprotein E knockout (ApoE-/-) mice. Male ApoE-/- mice were fed a high-fat diet with whole-grain highland barley (WHB) or refined highland barley for 18 weeks. WHB substantially inhibited the formation of atherosclerotic plaques, reduced serum tumor necrosis factor-α, and downregulated the expression of NLRP3 in the aorta. Furthermore, the 16S rRNA analysis revealed that highland barley supplementation helped to restore the dysregulation of the gut microbiota, as evidenced by an increase in the relative abundance of specific beneficial bacteria known for their anti-inflammatory properties, such as Lachnospiraceae, Lactobacillus, Muribaculaceae, and Bifidobacterium. Highland barley supplementation might alleviate atherosclerotic plaque formation by modulating the NLRP3 inflammasome pathway and the synthesis of anti-inflammatory metabolites by the gut microbiota.

Elderberry extract improves molecular markers of endothelial dysfunction linked to atherosclerosis.

Endothelial dysfunction (ED), secondary to diminished nitric oxide (NO) production and oxidative stress, is an early subclinical marker of atherosclerosis. Reduced NO bioavailability enhances the adhesion of monocytes to endothelial cells and promotes atherosclerosis. Elderberry extract (EB) is known to contain high levels of anthocyanins which could exert vascular protective effects. Specifically, we investigated the functional capacity of EB on various markers of ED. Human umbilical vein endothelial cells (HUVEC) were pretreated with EB 50 μg/mL and stimulated with TNF-α 10 ng/mL. Cell viability, apoptosis, oxidative stress; eNOS, Akt, Nrf2, NOX-4, and NF-κB at the protein level were measured. A co-culture model was used to determine whether EB could prevent the adhesion of monocytes (THP-1) to HUVECs. Moreover, the expression of adhesion molecules and pro-inflammatory cytokines were also measured. It wasdemonstrated that EB prevented TNF-α induced apoptosis and reactive oxygen species production in HUVECs. Additionally, EB upregulated Akt and eNOS activity, and Nrf2 expression in response to TNF-α, whereas it decreased NOX-4 expression and NF-κB activity. EB prevented the adhesion of monocytes to HUVECs, as well as reduced IL-6 and MCP-1 levels, which was associated with inhibition of VCAM-1 expression. Our results demonstrate that EB upregulates key cellular markers of endothelial function and ameliorates markers of ED. EB could be used as a potential nutritional aid for preventing atherosclerosis progression.

Experimental study on the optimization of ANM33 release in foam cells.

Given the miR-33's mechanistic relationships with multiple etiological factors in the pathogenesis of atherosclerosis (AS), we investigated the therapeutic potentials of dual-targeted microbubbles (HA-PANBs) in foam cell-specific release of anti-miR-33 (ANM33) oligonucleotides, resulting in the early prevention of AS progression and severity. The intracellular localization, loading optimization, and therapeutic effects of HA-PANBs were examined in detail in a co-cultured cell model of phagocytosis. Compared with non-targeting nanobubbles (NBs) and single-targeted microbubbles as controls, HA-PANBs efficiently delivered the ANM33 specifically to foam cells via sustained release, exhibiting its clinical value in mediating RNA silencing. Moreover, when used at a dose of 12 µg/mL HA-PANBs per 107 cells for 48 h, a higher release rate and drug efficacy were observed. Therefore, HA-PANBs, effectively targeting early AS foam cells, may represent a novel and optimal gene therapy approach for AS management.

Reducing Atherosclerotic Plaque Development and Endothelial Hemichannel Activity with WIN-55,212-2: A Research Protocol

Introduction: Endothelial cells (ECs) are critical regulators of vascular homeostasis, and their dysfunction leads to the development of atherosclerosis – the main underlying cause of cardiovascular diseases (CVDs). This dysfunction can be promoted by prolonged endothelial connexin43 hemichannel activity, which is caused by the combination of high glucose levels and cytokines IL-1β/TNF-α. WIN-55,212-2 (WIN) is a synthetic agonist of CB1/CB2 receptors and can counteract the proinflammatory effects of high glucose and IL-1β/TNF-α. We hypothesize that WIN treatment on ECs will reduce connexin43 hemichannel activity, thus preventing endothelial dysfunction and atherosclerotic progression. Methods: We will use the Apolipoprotein E Knockout (ApoE-/-) mouse model to assess the impact on atherosclerotic lesions. Hyperglycemia will be generated in these mice with Streptozotocin injections. The increased levels of glucose should induce IL-1β expression and stimulate prolonged hemichannel activity. ECs will be isolated from a subset of mice and cultured to test WIN-efficacy. ATP release will be assessed through an ATP viability assay. More in vitro assessments on subsets of ApoE-/- mice treated or not with WIN will be performed. Flow cytometry will evaluate monocyte-derived macrophage concentration and other pro and anti-inflammatory cytokines in tissue samples. Furthermore, atherosclerotic plaque volume in the aortic sinus will be quantified and characterized. Results: We expect that WIN-treated ECs will reduce ATP synthesis compared to those from the control group. Moreover, we expect to see a reduction in the inflammatory response with a consequent decrease in atherosclerotic progression. Discussion: This manuscript outlines the use of a novel compound that could prevent atherosclerosis progression. The results of this study could outline a potential mechanism that may be targeted to treat or forestall atherosclerosis progression. Conclusion: Overall, we aim to determine if WIN may not only hinder this pervasive condition but inhibit CVDs through curtailing atherosclerotic plaque development. The following steps include performing the experiment, confirming results through repetition, and using other animal models.

Heterocyclic Compounds as Dipeptidyl Peptidase-IV Inhibitors with Special Emphasis on Oxadiazoles as Potent Anti-Diabetic Agents.

Dipeptidyl peptidase-IV (DPP-IV) inhibitors, often known as gliptins, have been used to treat type 2 diabetes mellitus (T2DM). They may be combined with other medications as an additional treatment or used alone as a monotherapy. In addition to insulin, sulfonylureas, thiazolidinediones, and metformin, these molecules appear as possible therapeutic options. Oxadiazole rings have been employed in numerous different ways during drug development efforts. It has been shown that including them in the pharmacophore increases the amount of ligand that may be bound. The exceptional hydrogen bond acceptor properties of oxadiazoles and the distinct hydrocarbon bonding potential of their regioisomers have been established. Beside their anti-diabetic effects, oxadiazoles display a wide range of pharmacological properties. In this study, we made the assumption that molecules containing oxadiazole rings may afford a different approach to the treatment of diabetes, not only for controlling glycemic levels but also for preventing atherosclerosis progression and other complications associated with diabetes. It was observed that oxadiazole fusion with benzothiazole, 5-(2,5,2-trifluoroethoxy) phenyl, β-homophenylalanine, 2-methyl-2-{5-(4-chlorophenyl), diamine-bridged bis-coumarinyl, 5-aryl-2-(6′-nitrobenzofuran-2′-yl), nitrobenzofuran, and/or oxindole leads to potential anti-diabetic activity.

Understanding the role of alternative macrophage phenotypes in human atherosclerosis

Introduction Atherosclerosis-based ischemic heart disease is still the primary cause of death throughout the world. Over the past decades there has been no significant changes in the therapeutic approaches to atherosclerosis, which are mainly based on lipid lowering therapies and management of comorbid conditions such as diabetes and hypertension. The involvement of macrophages in atherosclerosis has been recognized for decades. More recently, a more detailed and sophisticated understanding of their various phenotypes and roles in the atherosclerotic process has been recognized. This new data is revealing how specific subtypes of macrophage-induced inflammation may have distinct effects on atherosclerosis progression and may provide new approaches for treatment, based upon targeting of specific macrophage subtypes. Areas covered We will comprehensively review the spectrum of macrophage phenotypes and how they contribute to atherosclerotic plaque development and progression. Expert opinion Various signals derived from atherosclerotic lesions drive macrophages into complex subsets with different gene expression profiles, phenotypes, and functions, not all of which are understood. Macrophage phenotypes include those that enhance, heal, and regress the atherosclerotic lesions though various mechanisms. Targeting of specific macrophage phenotypes may provide a promising and novel approach to prevent atherosclerosis progression.

Effects of Moderate Intensity Aerobic Exercise to FSTL-1 Regulation in Atherosclerosis: A Systematic Review.

Moderate intensity exercise is considered as a primary step to prevent coronary artery diseases (CADs) by stimulated FSTL-1 secretion as a novel myokines to improve endothelial cell function, prevent arterial stiffness, or vascular inflammation. This review aims to provide the current evident role of FSTL-1 as a novel myokine secreted during exercise to prevent atherosclerosis progression. A systematic review using databases from (PubMed), ScienceDirect, and The Cochrane Library, was conducted up to October 2021 to identify all the eligible experimental and observational studies that assess how moderate intensity exercises stimulate FSTL-1 secretion to prevent atherosclerosis. Results were described through narrative synthesis of the evidence. From 84 retrieved references, 15 studies met the inclusion criteria and were included in this review. The overall results suggest that exercise or physical activity can stimulate myokines secretion, especially in FSTL-1. FSTL-1 is a myokine or adipokine that plays a potential role in preventing atherosclerosis by various mechanisms such as via improvement of endothelial functions, suppression of smooth muscle cells (SMCs) proliferation, and reduction of arterial thickening. FSTL-1 is a relatively new and less known myokine, but probably holds a key role in assessing how moderate intensity aerobic exercise prevents atherosclerosis progression by preventing endothelial dysfunction, arterial stiffness, or vascular inflammation.

Abstract 421: Hematopoietic Deficiency In NLRP3 And AIM2 Inflammasomes Or Gasdermin D Fails To Prevent Atherosclerosis Progression In Mouse Models Of Diabetes

Diabetes accelerates atherosclerosis progression in part by increasing lesional necrotic core expansion, but the underlying mechanisms remain elusive. Previous studies have shown that systemic inhibition of the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome prevents atherosclerosis progression in a mouse model of diabetes. Gasdermin D (GSDMD), which acts downstream of inflammasome activation, contributes to pyroptosis and IL-1β and IL-18 release. To explore if hematopoietic inflammasome activation mediates diabetes-related necrotic core expansion, we first generated hematopoietic GSDMD-deficient chimeras in an LDL receptor-deficient ( Ldlr -/- ) virally-induced mouse model of type 1 diabetes (T1D)-accelerated atherosclerosis. Mice with T1D demonstrated elevated plasma glucose, triglycerides, cholesterol, and plasma IL-18 (non-diabetes [ND]=180.4 pg/ml, diabetes [D]=316.6, N=17-18 per group). However, diabetic mice with hematopoietic GSDMD-deficiency had no reduction in plasma IL-18 (D-KO=437.5 pg/ml, p=0.29, N=17). Moreover, we found little evidence of inflammasome activation in peritoneal and splenic macrophages from diabetic mice. A 4-week duration of diabetes significantly increased necrotic core area measured at three different levels in the aortic sinus (p<0.01, N=21-24 per group) in pre-existing lesions without increasing lesion area. Hematopoietic GSDMD-deficiency did not affect the necrotic core area. To further interrogate the relationship between hematopoietic inflammasome activation and diabetes-related necrotic core expansion, we generated Ldlr -/- hematopoietic NLRP3 and absent in melanoma 2 (AIM2) inflammasome double knockout (DKO) chimeras in a streptozotocin mouse model of diabetes. Mice with diabetes demonstrated hyperglycemia and hypercholesterolemia. However, diabetic hematopoietic DKO chimeras did not exhibit reduced aortic sinus necrotic core area, as compared with diabetic wildtype controls. Our findings suggest that the increased plasma IL-18 levels in diabetic mice are not dependent on hematopoietic GSDMD, and that diabetes-mediated necrotic core expansion is independent of hematopoietic NLRP3 and AIM2 inflammasome and pyroptosis pathways.

Triple-combined hypolipidaemic therapy in familial hypercholesterolaemia: clinical cases

Background. The prevalence of heterozygous familial hypercholesterolaemia (HeFH) comprises 1 per 250 people. The risk of premature cardiovascular disease (CVD) is 20 times higher in HeFH patients among the general population. CVD develops in HeFH patients under 20 years of age, and they usually do not survive to 30 years. Therefore, the primary treatment track here is correction of dyslipidaemia to prevent atherosclerosis progression and CVD. Clinical Case Descriptions. The article describes the clinical cases of familial dyslipidaemia in 47-yo patient M. and his 75-yo mother P. The patient had a visit related to blood pressure (BP) surges up to 140/90 mm Hg. In history: acute myocardial infarction (AMI) in maternal grandfather at 50 years and own uncle at 32 years. The patient’s cardiovascular risk factors: male gender, dyslipidaemia (total cholesterol (TC) 15.8 mmol/L), overweight (body mass index 29.9 kg/m2), familial history of young CVD, sedentary lifestyle (employed as manager), psychological and socioeconomic factors (work-related stress pressure), resting heart rate 88 beats/min. The patient was immediately ordered a combined hypolipidaemic therapy including rosuvastatin 20 mg, ezetimibe 10 mg, telmisartan 40 mg once daily for blood pressure correction. In 1-month therapy, cholesterol dropped to 4.4 mmol/L, low-density lipoprotein (LDL) cholesterol – to 2.2, but triglycerides remained high at 3.9 mmol/L. Fenofi brate added to therapy at 145 mg 1 time. Another 1-month therapy allowed the overall reduction of TC to 3.7, LDL cholesterol to 1.9, triglycerides to 2.17 and high-density lipoproteins to 1.19 mmol/L. Past 3 months, a further drop was observed in triglycerides to 1.7 mmol/L. Hence, a triple hypolipidaemic therapy facilitated the target LDL and triglyceride values without involving expensive medications like PCSK9 blockers. The patient’s mother also achieved the target basic lipidogram owing to a triple lipid-lowering therapy.Conclusion. The case is of interest to exemplify a successful triple lipid-lowering therapy in patients with familial hypercholesterolaemia.

Platinum-cerium bimetallic nano-raspberry for atherosclerosis treatment via synergistic foam cell inhibition and P2Y12 targeted antiplatelet aggregation

Massive platelet accumulation and foam cell production are critical in the development of atherosclerotic plaques. Although cardiovascular drugs can provide some relief from atherosclerotic disease, however, the efficacy is limited by first-pass and adverse effects. Herein, we designed a raspberry-liked platinum (Pt) and cerium (Ce) bimetallic nanostructures (PtCe NRs) with ticagrelor loading and PEGylation (DSPE-PEG2000-Ticagrelor-PtCe NRs, DPTP NRs), to weaken the plaques for atherosclerosis treatment via synergistic foam cell inhibition and antiplatelet aggregation. On one hand, the high surface roughness and area of the raspberry shaped structure endowed the bimetallic material amplified reactive oxygen species (ROS) scavenging activity to reduce the production of oxidized low-density lipoproteins in plaques, thus inhibiting the formation of foam cells. On the other hand, ticagrelor could act on the P2Y12 receptor in a non-competitive inhibitory manner to activate the P2Y12-ADCY-cAMP/p-VASP pathway, thereby restraining the massive platelets aggregation and preventing further plaque expansion. After 3 months treatment, the area of atherosclerotic lesions was significantly controlled in high fat diet-fed ApoE−/− mice. Besides, there was no obvious side effects during the treatment. These results demonstrated that DPTP NRs exhibited potential protective function for preventing atherosclerosis progression.

Lycopene Reduces Cholesterol Absorption and Prevents Atherosclerosis in ApoE-/- Mice by Downregulating HNF-1α and NPC1L1 Expression.

Our previous study showed that lycopene reduced the absorption of cholesterol in Caco-2 cells through inhibiting Niemann-Pick C1-Like 1 (NPC1L1) expression. Herein, we aimed to explore whether lycopene supplementation can decrease cholesterol absorption in the intestine and prevent atherosclerosis progression in high-fat diet (HFD)-fed apolipoprotein E knockout (ApoE-/-) mice. Male ApoE-/- mice were fed a high-fat diet with or without lycopene for 19 weeks. Supplementation of lycopene markedly lowered serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels. Additionally, serum high-density lipoprotein cholesterol (HDL-C) levels were increased after lycopene administration. Lycopene also downregulated the expression of NPC1L1 and hepatocyte nuclear factor-1α (HNF-1α) in the small intestine. Furthermore, the Oil Red O staining of the aorta and aortic sinus showed that lycopene supplementation remarkably reduced atherosclerotic lesions. These results indicated that lycopene inhibited intestinal cholesterol absorption and protected against HFD-induced atherosclerosis through inhibiting HNF-1α and NPC1L1 expression. Lycopene exhibits a potential antiatherosclerotic effect through suppressing intestinal cholesterol absorption.

Inducible phospholipid transfer protein deficiency ameliorates atherosclerosis

Background and aimsAtherosclerosis progression and regression studies are related to its prevention and treatment. Although we have gained extensive knowledge on germline phospholipid transfer protein (PLTP) deficiency, the effect of inducible PLTP deficiency in atherosclerosis remains unexplored. MethodsWe generated inducible PLTP (iPLTP)-knockout (KO) mice and measured their plasma lipid levels after feeding a normal chow or a Western-type diet. Adenovirus associated virus-proprotein convertase subtilisin/kexin type 9 (AAV-PCSK9) was used to induce hypercholesterolemia in the mice. Collars were placed around the common carotid arteries, and atherosclerosis progression and regression in the carotid arteries and aortic roots were evaluated. ResultsOn a normal chow diet, iPLTP-KO mice exhibited decreased cholesterol, phospholipid, apoA-I, and apoB levels compared with control mice. Furthermore, the overall amount of high-density lipoprotein (HDL) particles was reduced in these mice, but this effect was more profound for larger HDL particles. On a Western-type diet, iPLTP-KO mice again exhibited reduced levels of all tested lipids, even though the basal lipid levels were increased. Additionally, these mice displayed significantly reduced atherosclerotic plaque sizes with increased plaque stability. Importantly, inducible PLTP deficiency significantly ameliorated atherosclerosis by reducing the size of established plaques and the number of macrophages in the plaques without causing lipid accumulation in the liver. ConclusionsInduced PLTP deficiency in adult mice reduces plasma total cholesterol and triglycerides, prevents atherosclerosis progression, and promotes atherosclerosis regression. Thus, PLTP inhibition is a promising therapeutic approach for atherosclerosis.

Parnaparin in surgery, vascular surgery and associated disciplines

Aliterature review is dedicated to the use of Parnaparin in various surgical specialties. Prevention and treatment of thromboembolic complications is the major indication for the use of Parnaparin. In the review, the authors dwell on comparative studies of the efficacy oflow molecular weight heparins and unfractionated heparin. They also discuss in detail pharmacokinetics and pharmacodynamics of Parnaparin, its structure and effect on hemostasis components. Due tolack of direct comparative studies of variouslow molecular weight heparins, the authors provide reviews based on the network meta-analysis, which allowed them to identify the advantages of a specificlow molecular weight heparin by indirect comparison.There are few direct comparative studies of variouslow molecular weight heparins in theliterature, which does not allow for an objective assessment of their advantages and disadvantages. The authors do not only provideliterature data on direct comparative studies, but also show data on indirect comparisons (network meta-analysis). They analysed the efficacy of Parnaparin and otherlow molecular weight heparins for the prevention of thromboembolic complications, treatment of deep vein thrombosis and post-thrombophlebitic syndrome. The issues of the efficacy of Parnaparin in chronic arterial insufficiency and use in acute coronary syndrome are highlighted separately. The final part of the review is concerned with a promising, butlittle-known area of prophylaxis of restenosis and prevention of atherosclerosis progression. Experimental studies have allowed us to state that Parnaparin is one of the most effectivelow molecular weight heparins as far as thromboembolic complications are concerned. Parnaparin significantly reduces frequency of DVT events and, at the same time, decreases major bleeding risk as compared with unfractionated heparin. No dose adjustment is required in obese patients. Dose adjustments are based not on body weight but on risk factors for thrombosis, and obesity is only one of them to be considered to choose a dose. Amonglow molecular weight heparins, Parnaparin is one of the most potent drugs that reduces the proliferative and migratory capacity of smooth muscle cells; however, further research is needed to assess the prospects of using Parnaparin for the prevention of restenosis.

Salidroside simultaneously reduces de novo lipogenesis and cholesterol biosynthesis to attenuate atherosclerosis in mice

Salidroside is a kind of phenylethanoid glycoside and widespread in the plants from Rhodiola and Ligustrum species. Our previous study has reported that salidroside can prevent atherosclerosis progression by ameliorating glyerolipid and glycerophospholipid metabolism in apoE-deficient (apoE−/−) mice. However, its effect on neutral lipids and underlying mechanism remains largely unclear. Here we investigated the molecular mechanism of salidroside action from the perspective of metabolic regulation by integrating metabonomics and transcriptomics pattern. The results showed that salidroside significantly reduced cholesterols, esterified cholesterols, fatty acids, unsaturated fatty acids and triacylclycerols biosynthesis in liver through down-regulating the genes expressions of sterol regulatory element-binding proteins (Srebf1 and Srebf2). The expressions of SREBPs targeted and downstream genes, such as the encoding genes of fatty acid synthase (Fasn), glycerol-3-phosphate acyltransferase (Gpam), stearoyl-CoA desaturase (Scd), 3-hydroxy-3-methylglutaryl-CoA reductase (Hmgcr), and proprotein convertase subtilisin/kexin type 9 (Pcsk9), were also inhibited after salidroside administration. ATP citrate lyase gene (Acly) that encodes an important enzyme producing acetyl-CoA for cholesterol and fatty acid biosynthesis significantly decreased after treatment as well. Moreover, one of ketone body products, 3-hydroxybutyrate, was significantly up-regulated in drug-treated group, indicating that fatty acid degradation was accelerated by salidroside at the same time. Our findings identify salidroside as a regulator of lipid homeostasis in atherosclerotic mice, suggesting its potential to be an alternative medicine for lowering the risks of atherosclerosis-related diseases.

Tetrahydrobiopterin prevents chronic ischemia-related lower urinary tract dysfunction through the maintenance of nitric oxide bioavailability

This study aimed to investigate the influence of chronic ischemia on nitric oxide biosynthesis in the bladder and the effect of administering tetrahydrobiopterin (BH4), a cofactor for endothelial nitric oxide synthase (eNOS), on chronic ischemia-related lower urinary tract dysfunction (LUTD). This study divided male Sprague–Dawley rats into Control, chronic bladder ischemia (CBI) and CBI with oral BH4 supplementation (CBI/BH4) groups. In the CBI group, bladder capacity and bladder muscle strip contractility were significantly lower, and arterial wall was significantly thicker than in Controls. Significant improvements were seen in bladder capacity, muscle strip contractility and arterial wall thickening in the CBI/BH4 group as compared with the CBI group. Western blot analysis of bladder showed expressions of eNOS (p = 0.043), HIF-1α (p < 0.01) and dihydrofolate reductase (DHFR) (p < 0.01), which could regenerate BH4, were significantly higher in the CBI group than in Controls. In the CBI/BH4 group, HIF-1α (p = 0.012) and DHFR expressions (p = 0.018) were significantly decreased compared with the CBI group. Our results suggest that chronic ischemia increases eNOS and DHFR in the bladder to prevent atherosclerosis progression. However, DHFR could not synthesize sufficient BH4 relative to the increased eNOS, resulting in LUTD. BH4 supplementation protects lower urinary tract function by promoting eNOS activity.

Diabesity: the combined burden of obesity and diabetes on heart disease and the role of imaging.

Diabesity is a term used to describe the combined adverse health effects of obesity and diabetes mellitus. The worldwide dual epidemic of obesity and type 2 diabetes is an important public health issue. Projections estimate a sixfold increase in the number of adults with obesity in40 years and an increase in the number of individuals with diabetes to 642 million by 2040. Increased adiposity is the strongest risk factor for developing diabetes. Early detection of the effects of diabesity on the cardiovascular system would enable the optimal implementation of effective therapies that prevent atherosclerosis progression, cardiac remodelling, and the resulting ischaemic heart disease and heart failure. Beyond conventional imaging techniques, such as echocardiography, CT and cardiac magnetic resonance, novel post-processing tools and techniques provide information on the biological processes that underlie metabolic heart disease. In this Review, we summarize the effects of obesity and diabetes on myocardial structure and function and illustrate the use of state-of-the-art multimodality cardiac imaging to elucidate the pathophysiology of myocardial dysfunction, prognosticate long-term clinical outcomes and potentially guide treatment strategies.

HDAC1-mediated deacetylation of HIF1α prevents atherosclerosis progression by promoting miR-224-3p-mediated inhibition of FOSL2

We intended to characterize functional relevance of microRNA (miR)-224-3p in endothelial cell (EC) apoptosis and reactive oxygen species (ROS) accumulation in atherosclerosis, considering also the integral involvement of histone deacetylase 1 (HDAC1)-mediated hypoxia-inducible factor-1α (HIF1α) deacetylation. The binding affinity between miR-224-3p and Fos-like antigen 2 (FOSL2) was predicted and validated. Furthermore, we manipulated miR-224-3p, FOSL2, HDAC1, and HIF1α expression in oxidized low-density lipoprotein (ox-LDL)-induced ECs, aiming to clarify their effects on cell activities, inflammation, and ROS level. Additionally, we examined the impact of miR-224-3p on aortic atherosclerotic plaque and lesions in a high-fat-diet-induced atherosclerosis model in ApoE−/− mice. Clinical atherosclerotic samples and ox-LDL-induced human aortic ECs (HAECs) exhibited low HDAC1/miR-224-3p expression and high HIF1α/FOSL2 expression. miR-224-3p repressed EC cell apoptosis, inflammatory responses, and intracellular ROS levels through targeting FOSL2. HIF1α reduced miR-224-3p expression to accelerate EC apoptosis and ROS accumulation. Moreover, HDAC1 inhibited HIF1α expression by deacetylation, which in turn enhanced miR-224-3p expression to attenuate EC apoptosis and ROS accumulation. miR-224-3p overexpression reduced atherosclerotic lesions in vivo. In summary, HDAC1 overexpression may enhance the anti-atherosclerotic and endothelial-protective effects of miR-224-3p-mediated inhibition of FOSL2 by deacetylating HIF1α, underscoring a novel therapeutic insight against experimental atherosclerosis.

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

BackgroundStatins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats.MethodsSeven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated.ResultsAfter feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone.ConclusionsCombination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.