{"title":"Endothelial estrogen - myocardial cGMP axis critically determines angiogenesis and cardiac performance during pressure-overload","authors":"Nobuaki Fukuma, Hiroyuki Tokiwa, Genri Numata, Kazutaka Ueda, Pangyen Liu, Miyu Tajima, Yu Otsu, Taro Kariya, Yukio Hiroi, James K Liao, Issei Komuro, Eiki Takimoto","doi":"10.1093/cvr/cvae202","DOIUrl":"https://doi.org/10.1093/cvr/cvae202","url":null,"abstract":"Aim Estrogen exerts beneficial cardiovascular effects by binding to specific receptors on various cells to activate nuclear and non-nuclear actions. Estrogen receptor α (ERα) non-nuclear signaling confers protection against heart failure remodeling, involving myocardial cyclic guanosine monophosphate (cGMP) - cGMP-dependent protein kinase G (PKG) activation; however, its tissue-specific role remains elusive. Herein, we examined the cell type-specific role of ERα non-nuclear signaling in estrogen-conferred protection against heart failure. Methods and results We first assessed the tissue-specific impacts of ERα in estrogen’s cardiac benefits, utilizing endothelial ERα deletion (ERαf/f/Tie2Cre+) and myocyte ERα deletion (ERαf/f/αMHCCre+) female mice. Female mice were ovariectomized and the effect of estradiol (E2) was assessed in hearts exposed to 3week pressure-overload (TAC). E2 failed to improve cardiac function in ERαf/f/Tie2Cre+ TAC hearts but provided benefits in ERαf/f/αMHCCre+ TAC hearts, indicating that endothelial ERα is essential. We next assessed the role of non-nuclear signaling in endothelial cells, employing animals with endothelial-specific inactivation of ERα non-nuclear signaling (ERαKI/KI/Tie2Cre+). Female OVX mice were supplemented with E2 and subjected to 3-week TAC. ERαKI/KI/Tie2Cre+ TAC hearts revealed exacerbated cardiac dysfunction and reduced myocardial PKG activity as compared to littermate TAC hearts, which was associated with attenuated myocardial induction of vascular endothelial growth factor (VEGF) and angiogenesis as assessed with CD31-stained capillary density. This phenotype of ERαKI/KI/Tie2Cre+ was rescued by myocardial PKG activation from chronic treatment with soluble guanylate cyclase (sGC) stimulator. We performed co-culture experiments to determine endothelial-cardiomyocyte interactions. VEGF induction by E2 in cardiac myocytes required co-existence of intact endothelial ERα signaling in a NOS-dependent manner. On the other hand, VEGF was induced in myocytes directly with an sGC stimulator in the absence of endothelial cells. Conclusions An endothelial estrogen - myocardial cGMP axis stimulates angiogenic response and improves cardiac performance during pressure-overload.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"36 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142170807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Maternal folic acid over-supplementation impairs cardiac function in mice offspring by inhibiting SOD1 expression.","authors":"Ke Cai,Feng Wang,Hai-Qun Shi,An-Na Shen,Rui Zhao,Hao-Ran Geng,Jia-Quan Lu,Yong-Hao Gui,Yan Shi,Jian-Yuan Zhao","doi":"10.1093/cvr/cvae203","DOIUrl":"https://doi.org/10.1093/cvr/cvae203","url":null,"abstract":"BACKGROUNDFolic acid (FA) supplementation during pregnancy aims to protect foetal development. However, maternal over-supplementation of FA has been demonstrated to cause metabolic dysfunction and increase the risk of autism, retinoblastoma, and respiratory illness in the offspring. Moreover, FA supplementation reduces the risk of congenital heart disease. However, little is known about its possible adverse effects on cardiac health resulting from maternal over-supplementation. In this study, we assessed the detrimental effects of maternal FA over-supplementation on the cardiac health of the offspring.METHODS AND RESULTSEight-week-old C57BL/6J pregnant mice were randomly divided into control and over-supplemented groups. The offspring cardiac function was assessed using echocardiography. Cardiac fibrosis was assessed in the left ventricular myocardium by histological analysis. Proteomic, protein, RNA, and DNA methylation analyses were performed by liquid chromatography-tandem mass spectrometry, western blotting, real-time quantitative PCR, and bisulfite sequencing, respectively. We found that maternal periconceptional FA over-supplementation impaired cardiac function with the decreased left ventricular ejection fraction in the offspring. Biochemical indices and tissue staining further confirmed impaired cardiac function in offspring caused by maternal FA over-supplementation. The combined proteomic, RNA expression, and DNA methylation analyses suggested that key genes involved in cardiac function were inhibited at the transcriptional level possibly due to increased DNA methylation. Among these, superoxide dismutase 1 was downregulated, and reactive oxygen species (ROS) levels increased in the mouse heart. Inhibition of ROS generation using the antioxidant N-acetylcysteine rescued the impaired cardiac function resulting from maternal FA over-supplementation.CONCLUSIONSOur study revealed that over-supplementation with FA during mouse pregnancy is detrimental to cardiac function with the decreased left ventricular ejection fraction in the offspring and provides insights into the mechanisms underlying the association between maternal FA status and health outcomes in the offspring.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"57 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Xiaoxin Zhou,Chunyan Deng,Lin Chen,Lifu Lei,Xiaoliang Wang,Shuo Zheng,Caiyu Chen,Chengfeng Du,Valérie B Schini-Kerth,Jian Yang
{"title":"Zinc-alpha2-glycoprotein modulates blood pressure by regulating renal lipid metabolism reprogramming - mediated urinary Na+ excretion in hypertension.","authors":"Xiaoxin Zhou,Chunyan Deng,Lin Chen,Lifu Lei,Xiaoliang Wang,Shuo Zheng,Caiyu Chen,Chengfeng Du,Valérie B Schini-Kerth,Jian Yang","doi":"10.1093/cvr/cvae205","DOIUrl":"https://doi.org/10.1093/cvr/cvae205","url":null,"abstract":"AIMSOrgans modulating blood pressure are associated with a common cytokine known as adipokines. We chose Zinc-alpha2-glycoprotein (ZAG) due to its prioritized transcriptional level in the database. Previous studies showed that ZAG is involved in metabolic disorders. The aim of this study was to investigate its role in hypertension.METHODS AND RESULTSSerum ZAG levels were assessed in hypertensive and healthy participants. Blood pressure was monitored in Azgp1-/- mice and other animal models by 24-hour ambulatory implanted telemetric transmitters and tail-cuff method. Multi-omics analysis of proteomics and metabolomics were performed to explore possible mechanisms. Serum ZAG levels were significantly decreased and associated with morning urine Na+ excretion in hypertensive participants in a cross-sectional study. This study firstly reported that Azgp1-/- mice exhibited increased blood pressure and impaired urinary Na+ excretion, which were restored by AAV9-mediated renal tubule Azgp1 rescue. Azgp1 knockout caused the reprogramming of renal lipid metabolism, and increased Na+/H+-exchanger (NHE) activity in the renal cortex. Administration with a NHE inhibitor EIPA reversed the impaired urinary Na+ excretion in Azgp1-/- mice. Moreover, the activity of carnitine palmitoyltransferase 1 (CPT1), a key enzyme of fatty acid β-oxidation, was decreased, and the levels of malonyl-CoA, an inhibitor of CPT1, were increased in renal cortex of Azgp1-/- mice. Renal Cpt1 rescue improved urinary Na+ excretion and blood pressure in Azgp1-/- mice, accompanied by decreased renal fatty acid levels and NHE activity. Finally, administration of recombinant ZAG protein improved blood pressure and urinary Na+ excretion in SHRs.CONCLUSIONSDeficiency of Azgp1 increased the malonyl CoA-mediated inhibition of CPT1 activity, leading to renal lipid metabolism reprogramming, resulting in accumulated fatty acids and increased NHE activity, subsequently decreasing urinary Na+ excretion and causing hypertension. These findings may provide a potential kidney-targeted therapy in the prevention and treatment of hypertension.","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"34 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165882","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"REPRIEVE and CANTOS trials: lessons learned towards eliminating cardiovascular disease in human immunodeficiency virus by combined targeting of LDL and inflammation.","authors":"Annet Kirabo","doi":"10.1093/cvr/cvae152","DOIUrl":"https://doi.org/10.1093/cvr/cvae152","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":"54 1","pages":""},"PeriodicalIF":10.8,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142165910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aishwarya G Jacob, Ilias Moutsopoulous, Alex Petchey, Rafael Kollyfas, Vincent R Knight-Schrijver, Irina Mohorianu, Sanjay Sinha, Christopher W J Smith
{"title":"RBPMS promotes contractile phenotype splicing in human embryonic stem cell derived vascular smooth muscle cells.","authors":"Aishwarya G Jacob, Ilias Moutsopoulous, Alex Petchey, Rafael Kollyfas, Vincent R Knight-Schrijver, Irina Mohorianu, Sanjay Sinha, Christopher W J Smith","doi":"10.1093/cvr/cvae198","DOIUrl":"https://doi.org/10.1093/cvr/cvae198","url":null,"abstract":"<p><strong>Aims: </strong>Differentiated Vascular Smooth Muscle Cells (VSMCs) express a unique network of mRNA isoforms via smooth muscle specific alternative splicing (SM-AS) in functionally critical genes, including those comprising the contractile machinery. We previously described RNA Binding Protein Multiple Splicing (RBPMS) as a potent driver of differentiated SM-AS in the rat PAC1 VSMC cell line. What is unknown is how RBPMS affects VSMC phenotype and behaviour. Here, we aimed to dissect the role of RBPMS in SM-AS in human cells and determine the impact on VSMC phenotypic properties.</p><p><strong>Methods and results: </strong>We used human embryonic stem cell-derived VSMCs (hESC-VSMCs) as our platform. hESC-VSMCs are inherently immature and we found that they display only partially differentiated SM-AS patterns while RBPMS protein levels are low. We found that RBPMS overexpression induces SM-AS patterns in hESC-VSMCs akin to the contractile tissue VSMC splicing patterns. We present in silico and experimental findings that support RBPMS' splicing activity as mediated through direct binding and via functional cooperativity with splicing factor RBFOX2 on a significant subset of targets. We also demonstrate that RBPMS can alter the motility and the proliferative properties of hESC-VSMCs to mimic a more differentiated state.</p><p><strong>Conclusions: </strong>Overall, this study emphasizes a critical role for RBPMS in establishing the contractile phenotype splicing program of human VSMCs.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yoriko Heianza, Xuan Wang, Minghao Kou, Saumya Tiwari, Jeramie D Watrous, Kathryn M Rexrode, Mona Alotaibi, Mohit Jain, Qi Sun, JoAnn E Manson, Lu Qi
{"title":"Circulating dimethylguanidino valeric acid, dietary factors, and risk of coronary heart disease.","authors":"Yoriko Heianza, Xuan Wang, Minghao Kou, Saumya Tiwari, Jeramie D Watrous, Kathryn M Rexrode, Mona Alotaibi, Mohit Jain, Qi Sun, JoAnn E Manson, Lu Qi","doi":"10.1093/cvr/cvae199","DOIUrl":"https://doi.org/10.1093/cvr/cvae199","url":null,"abstract":"<p><strong>Aims: </strong>Circulating dimethylguanidino valeric acid (DMGV) was identified as a novel metabolite related to cardiorespiratory fitness and cardiometabolic abnormalities. Circulating DMGV levels are subjective to dietary modulation; however, studies on its associations with intakes of coronary heart disease (CHD)-related foods/nutrients are limited. We investigated whether plasma DMGV was related to risk of incident CHD. We tested associations of DMGV with CHD-related dietary intakes measured by 7-day dietary records and estimated corresponding disease risk.</p><p><strong>Methods and results: </strong>This nested case-control study on the incidence of CHD included 1520 women (760 incident cases of fatal CHD and nonfatal myocardial infarction and 760 controls) from the Nurses' Health Study. Separately, plasma DMGV and CHD-related dietary intakes and cardiometabolic abnormalities were assessed in the Women's Lifestyle Validation Study (WLVS; n=724). Higher plasma DMGV was related to a greater risk of CHD (relative risk [RR] per 1-SD: 1.26 [95% CI: 1.13, 1.40]; P-for-linearity=0.006). Greater intakes of sodium, energy dense-foods, and processed/red meat were related to higher DMGV levels; every 1-SD intake of sodium was associated with β 0.13 (SE 0.05; p=0.007) for DMGV-Z-scores, which corresponded to a RR of 1.031 [1.016, 1.046] for CHD. High DMGV (the top quartile, Q4) showed a significant RR of 1.60 [1.17, 2.18] after adjusting for diet and lifestyle factors; the RR further adjusting for obesity and hypertension was 1.29 [0.93, 1.79] as compared with the lowest quartile. In both cohorts, greater adiposity and adverse cardiometabolic factor status were significantly related to higher DMGV levels.</p><p><strong>Conclusion: </strong>Higher levels of plasma DMGV, a metabolite reflecting unfavorable CHD-related dietary intakes, were associated with an increased risk of CHD. The unfavorable association was attenuated by cardiometabolic risk factor status. Our study underscores the potential importance of plasma DMGV as an early biomarker associated with diet and the long-term risk of CHD among women.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2024-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142145276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maria Camacho-Encina, Laura K Booth, Rachael Redgrave, Minna Honkanen-Scott, William E Scott, Carmen Martin-Ruiz, Guy MacGowan, Sarah Richardson, John Dark, Simon Tual-Chalot, Gavin D Richardson
{"title":"Identifying optimal reference genes for qRT-PCR in human myocardial tissues.","authors":"Maria Camacho-Encina, Laura K Booth, Rachael Redgrave, Minna Honkanen-Scott, William E Scott, Carmen Martin-Ruiz, Guy MacGowan, Sarah Richardson, John Dark, Simon Tual-Chalot, Gavin D Richardson","doi":"10.1093/cvr/cvae194","DOIUrl":"https://doi.org/10.1093/cvr/cvae194","url":null,"abstract":"","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":""},"PeriodicalIF":10.2,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142139417","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rikeish R Muralitharan, Michael E Nakai, Matthew Snelson, Tenghao Zheng, Evany Dinakis, Liang Xie, Hamdi Jama, Madeleine Paterson, Waled Shihata, Flavia Wassef, Antony Vinh, Grant R Drummond, David M Kaye, Charles R Mackay, Francine Z Marques
{"title":"Influence of angiotensin II on the gut microbiome: modest effects in comparison to experimental factors.","authors":"Rikeish R Muralitharan, Michael E Nakai, Matthew Snelson, Tenghao Zheng, Evany Dinakis, Liang Xie, Hamdi Jama, Madeleine Paterson, Waled Shihata, Flavia Wassef, Antony Vinh, Grant R Drummond, David M Kaye, Charles R Mackay, Francine Z Marques","doi":"10.1093/cvr/cvae062","DOIUrl":"10.1093/cvr/cvae062","url":null,"abstract":"<p><strong>Aims: </strong>Animal models are regularly used to test the role of the gut microbiome in hypertension. Small-scale pre-clinical studies have investigated changes to the gut microbiome in the angiotensin II hypertensive model. However, the gut microbiome is influenced by internal and external experimental factors, which are not regularly considered in the study design. Once these factors are accounted for, it is unclear if microbiome signatures are reproduceable. We aimed to determine the influence of angiotensin II treatment on the gut microbiome using a large and diverse cohort of mice and to quantify the magnitude by which other factors contribute to microbiome variations.</p><p><strong>Methods and results: </strong>We conducted a retrospective study to establish a diverse mouse cohort resembling large human studies. We sequenced the V4 region of the 16S rRNA gene from 538 samples across the gastrointestinal tract of 303 male and female C57BL/6J mice randomized into sham or angiotensin II treatment from different genotypes, diets, animal facilities, and age groups. Analysing over 17 million sequencing reads, we observed that angiotensin II treatment influenced α-diversity (P = 0.0137) and β-diversity (i.e. composition of the microbiome, P < 0.001). Bacterial abundance analysis revealed patterns consistent with a reduction in short-chain fatty acid producers, microbial metabolites that lower blood pressure. Furthermore, animal facility, genotype, diet, age, sex, intestinal sampling site, and sequencing batch had significant effects on both α- and β-diversity (all P < 0.001). Sampling site (6.8%) and diet (6%) had the largest impact on the microbiome, while angiotensin II and sex had the smallest effect (each 0.4%).</p><p><strong>Conclusion: </strong>Our large-scale data confirmed findings from small-scale studies that angiotensin II impacted the gut microbiome. However, this effect was modest relative to most of the other factors studied. Accounting for these factors in future pre-clinical hypertensive studies will increase the likelihood that microbiome findings are replicable and translatable.</p>","PeriodicalId":9638,"journal":{"name":"Cardiovascular Research","volume":" ","pages":"1155-1163"},"PeriodicalIF":10.2,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11368123/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140189421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}