Pub Date : 2024-08-30Epub Date: 2024-07-29DOI: 10.1161/CIRCRESAHA.124.324272
Khaled Z Abd-Elmoniem, Jehad H Edwan, Katrina B Dietsche, Alfredo Villalobos-Perez, Nour Shams, Jatin Matta, Leilah Baumgarten, Waleed N Qaddumi, Sydney A Dixon, Aruba Chowdhury, Michael Stagliano, Lilian Mabundo, Annemarie Wentzel, Colleen Hadigan, Ahmed M Gharib, Stephanie T Chung
Background: Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.
Methods: Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate.
Results: Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells.
Conclusions: Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D.
Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.
{"title":"Endothelial Dysfunction in Youth-Onset Type 2 Diabetes: A Clinical Translational Study.","authors":"Khaled Z Abd-Elmoniem, Jehad H Edwan, Katrina B Dietsche, Alfredo Villalobos-Perez, Nour Shams, Jatin Matta, Leilah Baumgarten, Waleed N Qaddumi, Sydney A Dixon, Aruba Chowdhury, Michael Stagliano, Lilian Mabundo, Annemarie Wentzel, Colleen Hadigan, Ahmed M Gharib, Stephanie T Chung","doi":"10.1161/CIRCRESAHA.124.324272","DOIUrl":"10.1161/CIRCRESAHA.124.324272","url":null,"abstract":"<p><strong>Background: </strong>Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Endothelial function magnetic resonance imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using endothelial function magnetic resonance imaging, we evaluated peripheral and coronary artery structure and endothelial function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings.</p><p><strong>Methods: </strong>Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate.</p><p><strong>Results: </strong>Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; <i>P</i>=0.04) and impaired endothelial function: lower coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; <i>P</i><0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; <i>P</i>=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells.</p><p><strong>Conclusions: </strong>Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D.</p><p><strong>Registration: </strong>URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308 and NCT01399385.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11361354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141787368","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}
Pub Date : 2024-08-16Epub Date: 2024-07-22DOI: 10.1161/CIRCRESAHA.123.324139
Andreia Morais, Takahiko Imai, Xuyan Jin, Joseph J Locascio, Ligia Boisserand, Alison L Herman, Anjali Chauhan, Jessica Lamb, Karisma Nagarkatti, Marcio A Diniz, Mariia Kumskova, Nirav Dhanesha, Pradip K Kamat, Mohammad Badruzzaman Khan, Krishnan M Dhandapani, Rakesh B Patel, Brijesh Sutariya, Yanrong Shi, Klaus van Leyen, W Taylor Kimberly, David C Hess, Jaroslaw Aronowski, Enrique C Leira, Raymond C Koehler, Anil K Chauhan, Lauren H Sansing, Patrick D Lyden, Cenk Ayata
<p><strong>Background: </strong>The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.</p><p><strong>Methods: </strong>The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes.</p><p><strong>Results: </strong>Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes.</p><p><strong>Conclusions: </strong>Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivaria
{"title":"Biological and Procedural Predictors of Outcome in the Stroke Preclinical Assessment Network (SPAN) Trial.","authors":"Andreia Morais, Takahiko Imai, Xuyan Jin, Joseph J Locascio, Ligia Boisserand, Alison L Herman, Anjali Chauhan, Jessica Lamb, Karisma Nagarkatti, Marcio A Diniz, Mariia Kumskova, Nirav Dhanesha, Pradip K Kamat, Mohammad Badruzzaman Khan, Krishnan M Dhandapani, Rakesh B Patel, Brijesh Sutariya, Yanrong Shi, Klaus van Leyen, W Taylor Kimberly, David C Hess, Jaroslaw Aronowski, Enrique C Leira, Raymond C Koehler, Anil K Chauhan, Lauren H Sansing, Patrick D Lyden, Cenk Ayata","doi":"10.1161/CIRCRESAHA.123.324139","DOIUrl":"10.1161/CIRCRESAHA.123.324139","url":null,"abstract":"<p><strong>Background: </strong>The SPAN trial (Stroke Preclinical Assessment Network) is the largest preclinical study testing acute stroke interventions in experimental focal cerebral ischemia using endovascular filament middle cerebral artery occlusion (MCAo). Besides testing interventions against controls, the prospective design captured numerous biological and procedural variables, highlighting the enormous heterogeneity introduced by the multicenter structure that might influence stroke outcomes. Here, we leveraged the unprecedented sample size achieved by the SPAN trial and the prospective design to identify the biological and procedural variables that affect experimental stroke outcomes in transient endovascular filament MCAo.</p><p><strong>Methods: </strong>The study cohort included all mice enrolled and randomized in the SPAN trial (N=1789). Mice were subjected to 60-minute MCAo and followed for a month. Thirteen biological and procedural independent variables and 4 functional (weight loss and 4-point neuroscore on days 1 and 2, corner test on days 7 and 28, and mortality) and 3 tissue (day 2, magnetic resonance imaging infarct volumes and swelling; day 30, magnetic resonance imaging tissue loss) outcome variables were prospectively captured. Multivariable regression with stepwise elimination was used to identify the predictors and their effect sizes.</p><p><strong>Results: </strong>Older age, active circadian stage at MCAo, and thinner and longer filament silicone tips predicted higher mortality. Older age, larger body weight, longer anesthesia duration, and longer filament tips predicted worse neuroscores, while high-fat diet and blood flow monitoring predicted milder neuroscores. Older age and a high-fat diet predicted worse corner test performance. While shorter filament tips predicted more ipsiversive turning, longer filament tips appeared to predict contraversive turning. Age, sex, and weight interacted when predicting the infarct volume. Older age was associated with smaller infarcts on day 2 magnetic resonance imaging, especially in animals with larger body weights; this association was most conspicuous in females. High-fat diet also predicted smaller infarcts. In contrast, the use of cerebral blood flow monitoring and more severe cerebral blood flow drop during MCAo, longer anesthesia, and longer filament tips all predicted larger infarcts. Bivariate analyses among the dependent variables highlighted a disconnect between tissue and functional outcomes.</p><p><strong>Conclusions: </strong>Our analyses identified variables affecting endovascular filament MCAo outcome, an experimental stroke model used worldwide. Multiple regression refuted some commonly reported predictors and revealed previously unrecognized associations. Given the multicenter prospective design that represents a sampling of real-world conditions, the degree of heterogeneity mimicking clinical trials, the large number of predictors adjusted for in the multivaria","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11428171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141733667","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}
Pub Date : 2024-08-16Epub Date: 2024-07-11DOI: 10.1161/CIRCRESAHA.123.323970
Jin Hyuk Kim, Joon Woo Song, Yeon Hoon Kim, Hyun Jung Kim, Ryeong Hyun Kim, Ye Hee Park, Hyeong Soo Nam, Dong Oh Kang, Hongki Yoo, Kyeongsoon Park, Jin Won Kim
Background: Atherosclerosis is a chronic inflammatory disease causing a fatal plaque rupture, and its key aspect is a failure to resolve inflammation. We hypothesize that macrophage-targeted near-infrared fluorescence emitting photoactivation could simultaneously assess macrophage/lipid-rich plaques in vivo and facilitate inflammation resolution.
Methods: We fabricated a Dectin-1-targeted photoactivatable theranostic agent through the chemical conjugation of the near-infrared fluorescence-emitting photosensitizer chlorin e6 and the Dectin-1 ligand laminarin (laminarin-chlorin e6 [LAM-Ce6]). Intravascular photoactivation by a customized fiber-based diffuser after administration of LAM-Ce6 effectively reduced inflammation in the targeted plaques of atherosclerotic rabbits in vivo as serially assessed by dual-modal optical coherence tomography-near-infrared fluorescence structural-molecular catheter imaging after 4 weeks.
Results: The number of apoptotic macrophages peaked at 1 day after laser irradiation and then resolved until 4 weeks. Autophagy was strongly augmented 1 hour after the light therapy, with the formation of autophagolysosomes. LAM-Ce6 photoactivation increased the terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling/RAM11 (rabbit monocyte/macrophage antibody)- and MerTK (c-Mer tyrosine kinase)-positive cells in the plaques, suggesting enhanced efferocytosis. In line with inflammation resolution, photoactivation reduced the plaque burden through fibrotic replacement via the TGF (transforming growth factor)-β/CTGF (connective tissue growth factor) pathway.
Conclusions: Optical coherence tomography-near-infrared fluorescence imaging-guided macrophage Dectin-1-targetable photoactivation could induce the transition of macrophage/lipid-rich plaques into collagen-rich lesions through autophagy-mediated inflammation resolution and TGF-β-dependent fibrotic replacement. This novel strategy offers a new opportunity for the catheter-based theranostic strategy.
{"title":"Multimodal Imaging-Assisted Intravascular Theranostic Photoactivation on Atherosclerotic Plaque.","authors":"Jin Hyuk Kim, Joon Woo Song, Yeon Hoon Kim, Hyun Jung Kim, Ryeong Hyun Kim, Ye Hee Park, Hyeong Soo Nam, Dong Oh Kang, Hongki Yoo, Kyeongsoon Park, Jin Won Kim","doi":"10.1161/CIRCRESAHA.123.323970","DOIUrl":"10.1161/CIRCRESAHA.123.323970","url":null,"abstract":"<p><strong>Background: </strong>Atherosclerosis is a chronic inflammatory disease causing a fatal plaque rupture, and its key aspect is a failure to resolve inflammation. We hypothesize that macrophage-targeted near-infrared fluorescence emitting photoactivation could simultaneously assess macrophage/lipid-rich plaques in vivo and facilitate inflammation resolution.</p><p><strong>Methods: </strong>We fabricated a Dectin-1-targeted photoactivatable theranostic agent through the chemical conjugation of the near-infrared fluorescence-emitting photosensitizer chlorin e6 and the Dectin-1 ligand laminarin (laminarin-chlorin e6 [LAM-Ce6]). Intravascular photoactivation by a customized fiber-based diffuser after administration of LAM-Ce6 effectively reduced inflammation in the targeted plaques of atherosclerotic rabbits in vivo as serially assessed by dual-modal optical coherence tomography-near-infrared fluorescence structural-molecular catheter imaging after 4 weeks.</p><p><strong>Results: </strong>The number of apoptotic macrophages peaked at 1 day after laser irradiation and then resolved until 4 weeks. Autophagy was strongly augmented 1 hour after the light therapy, with the formation of autophagolysosomes. LAM-Ce6 photoactivation increased the terminal deoxynucleotidyl transferase dUTP (deoxyuridine triphosphate) nick end labeling/RAM11 (rabbit monocyte/macrophage antibody)- and MerTK (c-Mer tyrosine kinase)-positive cells in the plaques, suggesting enhanced efferocytosis. In line with inflammation resolution, photoactivation reduced the plaque burden through fibrotic replacement via the TGF (transforming growth factor)-β/CTGF (connective tissue growth factor) pathway.</p><p><strong>Conclusions: </strong>Optical coherence tomography-near-infrared fluorescence imaging-guided macrophage Dectin-1-targetable photoactivation could induce the transition of macrophage/lipid-rich plaques into collagen-rich lesions through autophagy-mediated inflammation resolution and TGF-β-dependent fibrotic replacement. This novel strategy offers a new opportunity for the catheter-based theranostic strategy.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141579121","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}
Pub Date : 2024-08-16Epub Date: 2024-08-15DOI: 10.1161/CIRCRESAHA.124.325130
Leandro Santiago Padilla, Gabriele G Schiattarella
{"title":"Targeting HFpEF: Unlocking the Potential of Glucagon Receptor Blockade.","authors":"Leandro Santiago Padilla, Gabriele G Schiattarella","doi":"10.1161/CIRCRESAHA.124.325130","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325130","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987530","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}
Pub Date : 2024-08-16Epub Date: 2024-07-16DOI: 10.1161/CIRCRESAHA.124.324706
Chen Gao, Zhaojun Xiong, Yunxia Liu, Meng Wang, Menglong Wang, Tian Liu, Jianfang Liu, Shuxun Ren, Nancy Cao, Hai Yan, Daniel J Drucker, Christoph Daniel Rau, Tomohiro Yokota, Jijun Huang, Yibin Wang
Background: Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized.
Method: We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lepob/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts.
Results: In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress.
Conclusions: These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.
{"title":"Glucagon Receptor Antagonist for Heart Failure With Preserved Ejection Fraction.","authors":"Chen Gao, Zhaojun Xiong, Yunxia Liu, Meng Wang, Menglong Wang, Tian Liu, Jianfang Liu, Shuxun Ren, Nancy Cao, Hai Yan, Daniel J Drucker, Christoph Daniel Rau, Tomohiro Yokota, Jijun Huang, Yibin Wang","doi":"10.1161/CIRCRESAHA.124.324706","DOIUrl":"10.1161/CIRCRESAHA.124.324706","url":null,"abstract":"<p><strong>Background: </strong>Heart failure with preserved ejection fraction (HFpEF) is an emerging major unmet need and one of the most significant clinic challenges in cardiology. The pathogenesis of HFpEF is associated with multiple risk factors. Hypertension and metabolic disorders associated with obesity are the 2 most prominent comorbidities observed in patients with HFpEF. Although hypertension-induced mechanical overload has long been recognized as a potent contributor to heart failure with reduced ejection fraction, the synergistic interaction between mechanical overload and metabolic disorders in the pathogenesis of HFpEF remains poorly characterized.</p><p><strong>Method: </strong>We investigated the functional outcome and the underlying mechanisms from concurrent mechanic and metabolic stresses in the heart by applying transverse aortic constriction in lean C57Bl/6J or obese/diabetic B6.Cg-Lep<sup>ob</sup>/J (ob/ob) mice, followed by single-nuclei RNA-seq and targeted manipulation of a top-ranked signaling pathway differentially affected in the 2 experimental cohorts.</p><p><strong>Results: </strong>In contrast to the post-transverse aortic constriction C57Bl/6J lean mice, which developed pathological features of heart failure with reduced ejection fraction over time, the post-transverse aortic constriction ob/ob mice showed no significant changes in ejection fraction but developed characteristic pathological features of HFpEF, including diastolic dysfunction, worsened cardiac hypertrophy, and pathological remodeling, along with further deterioration of exercise intolerance. Single-nuclei RNA-seq analysis revealed significant transcriptome reprogramming in the cardiomyocytes stressed by both pressure overload and obesity/diabetes, markedly distinct from the cardiomyocytes singularly stressed by pressure overload or obesity/diabetes. Furthermore, glucagon signaling was identified as the top-ranked signaling pathway affected in the cardiomyocytes associated with HFpEF. Treatment with a glucagon receptor antagonist significantly ameliorated the progression of HFpEF-related pathological features in 2 independent preclinical models. Importantly, cardiomyocyte-specific genetic deletion of the glucagon receptor also significantly improved cardiac function in response to pressure overload and metabolic stress.</p><p><strong>Conclusions: </strong>These findings identify glucagon receptor signaling in cardiomyocytes as a critical determinant of HFpEF progression and provide proof-of-concept support for glucagon receptor antagonism as a potential therapy for the disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11325917/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141619463","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}
Pub Date : 2024-08-16Epub Date: 2024-07-23DOI: 10.1161/CIRCRESAHA.124.324823
Justin H Berger, Timothy R Matsuura, Caitlyn E Bowman, Renee Taing, Jiten Patel, Ling Lai, Teresa C Leone, Jeffrey D Reagan, Saptarsi M Haldar, Zoltan Arany, Daniel P Kelly
{"title":"SGLT2 Inhibitors Act Independently of SGLT2 to Confer Benefit for HFrEF in Mice.","authors":"Justin H Berger, Timothy R Matsuura, Caitlyn E Bowman, Renee Taing, Jiten Patel, Ling Lai, Teresa C Leone, Jeffrey D Reagan, Saptarsi M Haldar, Zoltan Arany, Daniel P Kelly","doi":"10.1161/CIRCRESAHA.124.324823","DOIUrl":"10.1161/CIRCRESAHA.124.324823","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11326968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141747479","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}
Background: Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response.
Methods: In this study, we used single-cell RNA-sequencing analysis of Cd45+CD11b+F4/80+ cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2+ (C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation.
Results: We find that the Ccr2 cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2+CX3CR1+ macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the RelA promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity.
Conclusions: Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.
{"title":"Lysozyme 1 Inflamed CCR2<sup>+</sup> Macrophages Promote Obesity-Induced Cardiac Dysfunction.","authors":"Lai Zhang, Huian Han, Andi Xu, Adwait Sathe, Siying Fu, Jiaqi Zhao, Wenhan Cai, Yaqing Yang, Jinting Liu, Hui Bai, Jingjing Ben, Xudong Zhu, Xiaoyu Li, Qing Yang, Zidun Wang, Yayun Gu, Chao Xing, Gabriele G Schiattarella, Steven Yan Cheng, Hanwen Zhang, Qi Chen","doi":"10.1161/CIRCRESAHA.124.324106","DOIUrl":"10.1161/CIRCRESAHA.124.324106","url":null,"abstract":"<p><strong>Background: </strong>Macrophages are key players in obesity-associated cardiovascular diseases, which are marked by inflammatory and immune alterations. However, the pathophysiological mechanisms underlying macrophage's role in obesity-induced cardiac inflammation are incompletely understood. Our study aimed to identify the key macrophage population involved in obesity-induced cardiac dysfunction and investigate the molecular mechanism that contributes to the inflammatory response.</p><p><strong>Methods: </strong>In this study, we used single-cell RNA-sequencing analysis of Cd45<sup>+</sup>CD11b<sup>+</sup>F4/80<sup>+</sup> cardiac macrophages to explore the heterogeneity of cardiac macrophages. The CCR2<sup>+</sup> (C-C chemokine receptor 2) macrophages were specifically removed by a dual recombinase approach, and the macrophage CCR2 was deleted to investigate their functions. We also performed cleavage under target and tagmentation analysis, chromatin immunoprecipitation-polymerase chain reaction, luciferase assay, and macrophage-specific lentivirus transfection to define the impact of lysozyme C in macrophages on obesity-induced inflammation.</p><p><strong>Results: </strong>We find that the <i>Ccr2</i> cluster undergoes a functional transition from homeostatic maintenance to proinflammation. Our data highlight specific changes in macrophage behavior during cardiac dysfunction under metabolic challenge. Consistently, inducible ablation of CCR2<sup>+</sup>CX3CR1<sup>+</sup> macrophages or selective deletion of macrophage CCR2 prevents obesity-induced cardiac dysfunction. At the mechanistic level, we demonstrate that the obesity-induced functional shift of CCR2-expressing macrophages is mediated by the CCR2/activating transcription factor 3/lysozyme 1/NF-κB (nuclear factor kappa B) signaling. Finally, we uncover a noncanonical role for lysozyme 1 as a transcription activator, binding to the <i>RelA</i> promoter, driving NF-κB signaling, and strongly promoting inflammation and cardiac dysfunction in obesity.</p><p><strong>Conclusions: </strong>Our findings suggest that lysozyme 1 may represent a potential target for the diagnosis of obesity-induced inflammation and the treatment of obesity-induced heart disease.</p>","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141757433","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}
Pub Date : 2024-08-16Epub Date: 2024-08-15DOI: 10.1161/RES.0000000000000687
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000687","DOIUrl":"https://doi.org/10.1161/RES.0000000000000687","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987529","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}
Pub Date : 2024-08-16Epub Date: 2024-08-15DOI: 10.1161/RES.0000000000000687
{"title":"Meet the First Authors.","authors":"","doi":"10.1161/RES.0000000000000687","DOIUrl":"https://doi.org/10.1161/RES.0000000000000687","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142035420","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}
Pub Date : 2024-08-16Epub Date: 2024-08-15DOI: 10.1161/CIRCRESAHA.124.325129
Matthias Endres, Nikolaus Plesnila, Johannes Boltze
{"title":"Variables Predicting Experimental Stroke Outcome: How Well Do We Know Our Models?","authors":"Matthias Endres, Nikolaus Plesnila, Johannes Boltze","doi":"10.1161/CIRCRESAHA.124.325129","DOIUrl":"https://doi.org/10.1161/CIRCRESAHA.124.325129","url":null,"abstract":"","PeriodicalId":10147,"journal":{"name":"Circulation research","volume":null,"pages":null},"PeriodicalIF":16.5,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987531","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}