Cardiology
Abstract
BACKGROUND. Systemic lupus erythematosus (SLE) is associated with enhanced risk of atherosclerotic cardiovascular disease not explained by Framingham risk score (FRS). Immune dysregulation associated to a distinct subset of lupus proinflammatory neutrophils (low density granulocytes; LDGs) may play key roles in conferring enhanced CV risk. This study assessed if lupus LDGs are associated with in vivo vascular dysfunction and inflammation and coronary plaque. METHODS. SLE subjects and healthy controls underwent multimodal phenotyping of vascular disease by quantifying vascular inflammation (18F-fluorodeoxyglucose–PET/CT [18F-FDG–PET/CT]), arterial dysfunction (EndoPAT and cardio-ankle vascular index), and coronary plaque burden (coronary CT angiography). LDGs were quantified by flow cytometry. Cholesterol efflux capacity was measured in high-density lipoprotein–exposed (HDL-exposed) radioactively labeled cell lines. Whole blood RNA sequencing was performed to assess associations between transcriptomic profiles and vascular phenotype. RESULTS. Vascular inflammation, arterial stiffness, and noncalcified plaque burden (NCB) were increased in SLE compared with controls even after adjustment for traditional risk factors. In SLE, NCB directly associated with LDGs and associated negatively with cholesterol efflux capacity in fully adjusted models. A neutrophil gene signature reflective of the most upregulated genes in lupus LDGs associated with vascular inflammation and NCB. CONCLUSION. Individuals with SLE demonstrate vascular inflammation, arterial dysfunction, and NCB, which may explain the higher reported risk for acute coronary syndromes. The association of LDGs and neutrophil genes with vascular disease supports the hypothesis that distinct neutrophil subsets contribute to vascular damage and unstable coronary plaque in SLE. Results also support previous observations that neutrophils may disrupt HDL function and thereby promote atherogenesis. TRIAL REGISTRATION. Clinicaltrials.gov NCT00001372 FUNDING. Intramural Research Program NIAMS/NIH (ZIA AR041199) and Lupus Research Institute
Authors
Philip M. Carlucci, Monica M. Purmalek, Amit K. Dey, Yenealem Temesgen-Oyelakin, Simantini Sakhardande, Aditya A. Joshi, Joseph B. Lerman, Alice Fike, Michael Davis, Jonathan H. Chung, Martin P. Playford, Mohammad Naqi, Pragnesh Mistry, Gustavo Gutierrez-Cruz, Stefania Dell’Orso, Faiza Naz, Taufiq Salahuddin, Balaji Natarajan, Zerai Manna, Wanxia L. Tsai, Sarthak Gupta, Peter Grayson, Heather Teague, Marcus Y. Chen, Hong-Wei Sun, Sarfaraz Hasni, Nehal N. Mehta, Mariana J. Kaplan
Abstract
Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation–bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-β signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-β signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti–TGF-β signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM.
Authors
Styliani Vakrou, Ryuya Fukunaga, D. Brian Foster, Lars Sorensen, Yamin Liu, Yufan Guan, Kirubel Woldemichael, Roberto Pineda-Reyes, Ting Liu, Jill C. Tardiff, Leslie A. Leinwand, Carlo G. Tocchetti, Theodore P. Abraham, Brian O’Rourke, Miguel A. Aon, M. Roselle Abraham
Abstract
Using an untargeted metabolomics approach in initial (N = 99 subjects) and replication cohorts (N = 1,162), we discovered and structurally identified a plasma metabolite associated with cardiovascular disease (CVD) risks, N6,N6,N6-trimethyl-L-lysine (trimethyllysine, TML). Stable-isotope-dilution tandem mass spectrometry analyses of an independent validation cohort (N = 2,140) confirmed TML levels are independently associated with incident (3-year) major adverse cardiovascular event risks (hazards ratio [HR], 2.4; 95% CI, 1.7–3.4) and incident (5-year) mortality risk (HR, 2.9; 95% CI, 2.0–4.2). Genome-wide association studies identified several suggestive loci for TML levels, but none reached genome-wide significance; and d9(trimethyl)-TML isotope tracer studies confirmed TML can serve as a nutrient precursor for gut microbiota–dependent generation of trimethylamine (TMA) and the atherogenic metabolite trimethylamine N-oxide (TMAO). Although TML was shown to be abundant in both plant- and animal-derived foods, mouse and human fecal cultures (omnivores and vegans) showed slow conversion of TML to TMA. Furthermore, unlike chronic dietary choline, TML supplementation in mice failed to elevate plasma TMAO or heighten thrombosis potential in vivo. Thus, TML is identified as a strong predictor of incident CVD risks in subjects and to serve as a dietary precursor for gut microbiota–dependent generation of TMAO; however, TML does not appear to be a major microbial source for TMAO generation in vivo.
Authors
Xinmin S. Li, Zeneng Wang, Tomas Cajka, Jennifer A. Buffa, Ina Nemet, Alex G. Hurd, Xiaodong Gu, Sarah M. Skye, Adam B. Roberts, Yuping Wu, Lin Li, Christopher J. Shahen, Matthew A. Wagner, Jaana A. Hartiala, Robert L. Kerby, Kymberleigh A. Romano, Yi Han, Slayman Obeid, Thomas F. Lüscher, Hooman Allayee, Federico E. Rey, Joseph A. DiDonato, Oliver Fiehn, W.H. Wilson Tang, Stanley L. Hazen
Abstract
Loss-of-function mutations in genes encoding contractile proteins have been observed in thoracic aortic aneurysms (TAA). To gain insight into the contribution of contractile protein deficiency in the pathogenesis of TAA, we examined human aneurysm samples. We found multiple contractile gene products deficient in TAA samples, and in particular, expression of SM22α was inversely correlated with aneurysm size. SM22α-deficient mice demonstrated pregnancy-induced aortic dissection, and SM22α deficiency worsened aortic aneurysm in Fbn1C1039G/+ (Marfan) mice, validating this gene product as a TAA effector. We found that repression of SM22α was enforced by increased activity of the methyltransferase EZH2. TGF-β effectors such as SMAD3 were excluded from binding SM22α-encoding chromatin (TAGLN) in TAA samples, while treatment with the EZH2 inhibitor GSK343 improved cytoskeletal architecture and restored SM22α expression. Finally, inhibition of EZH2 improved aortic performance in Fbn1C1039G/+ mice, in association with restoration of contractile protein expression (including SM22α). Together, these data inform our understanding of contractile protein deficiency in TAA and support the pursuit of chromatin modifying factors as therapeutic targets in aortic disease.
Authors
Christian L. Lino Cardenas, Chase W. Kessinger, Carolyn MacDonald, Arminder S. Jassar, Eric M. Isselbacher, Farouc A. Jaffer, Mark E. Lindsay
Abstract
Myocardial infarctions (MIs) cause the loss of myocytes due to lack of sufficient oxygenation and latent revascularization. Although the administration of histone deacetylase (HDAC) inhibitors reduces the size of infarctions and improves cardiac physiology in small-animal models of MI injury, the cellular targets of the HDACs, which the drugs inhibit, are largely unspecified. Here, we show that WNT-inducible secreted protein-1 (Wisp-1), a matricellular protein that promotes angiogenesis in cancers as well as cell survival in isolated cardiac myocytes and neurons, is a target of HDACs. Further, Wisp-1 transcription is regulated by HDACs and can be modified by the HDAC inhibitor, suberanilohydroxamic acid (SAHA/vorinostat), after MI injury. We observe that, at 7 days after MI, Wisp-1 is elevated 3-fold greater in the border zone of infarction in mice that experience an MI injury and are injected daily with SAHA, relative to MI alone. Additionally, human coronary artery endothelial cells (HCAECs) produce WISP-1 and are responsive to autocrine WISP-1–mediated signaling, which functionally promotes their proangiogenic behavior. Altering endogenous expression of WISP-1 in HCAECs directly impacts their network density in vitro. Therapeutic interventions after a heart attack define the extent of infarct injury, cell survival, and overall prognosis. Our studies shown here identify a potentially novel cardiac angiokine, Wisp-1, that may contribute to beneficial post-MI treatment modalities.
Authors
Lillianne H. Wright, Daniel J. Herr, Symone S. Brown, Harinath Kasiganesan, Donald R. Menick
Abstract
Heart failure with preserved ejection fraction (HFpEF) can arise from cardiac and vascular remodeling processes following long-lasting hypertension. Efficacy of common HF therapeutics is unsatisfactory in HFpEF. Evidence suggests that stimulators of the nitric oxide–sensitive soluble guanylyl cyclase (NOsGC) could be of use here. We aimed to characterize the complex cardiovascular effects of NOsGC stimulation using NO-independent stimulator BAY 41-8543 in a double-transgenic rat (dTGR) model of HFpEF. We show a drastically improved survival rate of treated dTGR. We observed less cardiac fibrosis, macrophage infiltration, and gap junction remodeling in treated dTGR. Microarray analysis revealed that treatment of dTGR corrected the dysregulateion of cardiac genes associated with fibrosis, inflammation, apoptosis, oxidative stress, and ion channel function toward an expression profile similar to healthy controls. Treatment reduced systemic blood pressure levels and improved endothelium-dependent vasorelaxation of resistance vessels. Further comprehensive in vivo phenotyping showed an improved diastolic cardiac function, improved hemodynamics, and less susceptibility to ventricular arrhythmias. Short-term BAY 41-8543 application in isolated untreated transgenic hearts with structural remodeling significantly reduced the occurrence of ventricular arrhythmias, suggesting a direct nongenomic role of NOsGC stimulation on excitation. Thus, NOsGC stimulation was highly effective in improving several HFpEF facets in this animal model, underscoring its potential value for patients.
Authors
Nicola Wilck, Lajos Markó, András Balogh, Kristin Kräker, Florian Herse, Hendrik Bartolomaeus, István A. Szijártó, Maik Gollasch, Nadine Reichhart, Olaf Strauss, Arnd Heuser, Damian Brockschnieder, Axel Kretschmer, Ralf Lesche, Florian Sohler, Johannes-Peter Stasch, Peter Sandner, Friedrich C. Luft, Dominik N. Müller, Ralf Dechend, Nadine Haase
Abstract
The role of proinflammation, and specifically TNF-α, on downstream fibrosis and healing after cardiac injury remains unknown. Using iRhom2-deficient mice, which lack myeloid-specific shedding of TNF-α, we reveal increased macrophages (MΦs) that were skewed towards a more proinflammatory (M1) state at day 4, followed by more reparative, antiinflammatory (M2) state at day 7 after myocardial infarction (MI). However, associated functional cytokine expression was significantly reduced in iRhom2-mutant M1 and M2 MΦs, respectively. A dampened proinflammatory signature in iRhom2-deficient mice during the acute phase of injury and subsequent changes in MΦ polarization were associated with reduced phagocytosis and a more sparse distribution within the scar region. This resulted in impaired collagen deposition and fibrosis, and increased left ventricular remodelling and mortality in iRhom2-deficient mice after MI. Our findings reveal a requirement for an iRhom2-mediated proinflammatory response during downstream scarring and fibrosis, which is driven in part by TNF-α signaling. These conclusions challenge the existing model that infarct repair is determined exclusively by antiinflammatory signaling of M2 MΦs, and as such we propose an alternative view of immunomodulation to maintain effective healing after infarction.
Authors
Damien N. Barnette, Thomas J. Cahill, Mala Gunadasa-Rohling, Carolyn A. Carr, Matthew Freeman, Paul R. Riley
Abstract
To elucidate the mechanisms responsible for cytoprotective effects of TNF receptor–activated factor 2 (TRAF2) in the heart, we employed genetic gain- and loss-of-function studies ex vivo and in vivo in mice with cardiac-restricted overexpression of TRAF2 (Myh6-TRAF2LC). Crossing Myh6-TRAF2LC mice with mice lacking canonical signaling (Myh6-TRAF2LC/Myh6-IκBαΔN) abrogated the cytoprotective effects of TRAF2 ex vivo. In contrast, inhibiting the JAK/STAT pathway did not abrogate the cytoprotective effects of TRAF2. Transcriptional profiling of WT, Myh6-TRAF2LC, and Myh6-TRAF2LC/Myh6-IκBαΔN mouse hearts suggested that the noncanonical NF-κB signaling pathway was upregulated in the Myh6-TRAF2LC mouse hearts. Western blotting and ELISA for the NF-κB family proteins p50, p65, p52, and RelB on nuclear and cytoplasmic extracts from naive 12-week-old WT, Myh6-TRAF2LC, and Myh6-TRAF2LC/Myh6-IκBαΔN mouse hearts showed increased expression levels and increased DNA binding of p52 and RelB, whereas there was no increase in expression or DNA binding of the p50 and p65 subunits. Crossing Myh6-TRAF2LC mice with RelB–/+ mice (Myh6-TRAF2LC/RelB–/+) attenuated the cytoprotective effects of TRAF2 ex vivo and in vivo. Viewed together, these results suggest that crosstalk between the canonical and noncanonical NF-κB signaling pathways is required for mediating the cytoprotective effects of TRAF2.
Authors
Sarah Evans, Huei-Ping Tzeng, Deborah J. Veis, Scot Matkovich, Carla Weinheimer, Attila Kovacs, Philip M. Barger, Douglas L. Mann
Abstract
Anthracyclines such as doxorubicin are highly effective chemotherapy agents used to treat many common malignancies. However, their use is limited by cardiotoxicity. We previously identified visnagin as protecting against doxorubicin toxicity in cardiac but not tumor cells. In this study, we sought to develop more potent visnagin analogs in order to use these analogs as tools to clarify the mechanisms of visnagin-mediated cardioprotection. Structure-activity relationship studies were performed in a zebrafish model of doxorubicin cardiomyopathy. Movement of the 5-carbonyl to the 7 position and addition of short ester side chains led to development of visnagin analogs with 1,000-fold increased potency in zebrafish and 250-fold increased potency in mice. Using proteomics, we discovered that doxorubicin caused robust induction of Cytochrome P450 family 1 (CYP1) that was mitigated by visnagin and its potent analog 23. Treatment with structurally divergent CYP1 inhibitors, as well as knockdown of CYP1A, prevented doxorubicin cardiomyopathy in zebrafish. The identification of potent cardioprotective agents may facilitate the development of new therapeutic strategies for patients receiving cardiotoxic chemotherapy. Moreover, these studies support the idea that CYP1 is an important contributor to doxorubicin cardiotoxicity and suggest that modulation of this pathway could be beneficial in the clinical setting.
Authors
Aarti Asnani, Bahoui Zheng, Yan Liu, You Wang, Howard H. Chen, Anita Vohra, An Chi, Ivan Cornella-Taracido, Huijun Wang, Douglas G. Johns, David E. Sosnovik, Randall T. Peterson
Abstract
Inflammation is critical to atherogenesis. Psoriasis is a chronic inflammatory skin disease that accelerates atherosclerosis in humans and provides a compelling model to understand potential pathways linking these diseases. A murine model capturing the vascular and metabolic diseases in psoriasis would accelerate our understanding and provide a platform to test emerging therapies. We aimed to characterize a new murine model of skin inflammation (Rac1V12) from a cardiovascular standpoint to identify novel atherosclerotic signaling pathways modulated in chronic skin inflammation. The RacV12 psoriasis mouse resembled the human disease state, including presence of systemic inflammation, dyslipidemia, and cardiometabolic dysfunction. Psoriasis macrophages had a proatherosclerotic phenotype with increased lipid uptake and foam cell formation, and also showed a 6-fold increase in cholesterol crystal formation. We generated a triple-genetic K14-RacV12–/+/Srb1–/–/ApoER61H/H mouse and confirmed psoriasis accelerates atherogenesis (~7-fold increase). Finally, we noted a 60% reduction in superoxide dismutase 2 (SOD2) expression in human psoriasis macrophages. When SOD2 activity was restored in macrophages, their proatherogenic phenotype reversed. We demonstrate that the K14-RacV12 murine model captures the cardiometabolic dysfunction and accelerates vascular disease observed in chronic inflammation and that skin inflammation induces a proatherosclerotic macrophage phenotype with impaired SOD2 function, which associated with accelerated atherogenesis.
Authors
Yvonne Baumer, Qimin Ng, Gregory E. Sanda, Amit K. Dey, Heather L. Teague, Alexander V. Sorokin, Pradeep K. Dagur, Joanna I. Silverman, Charlotte L. Harrington, Justin A. Rodante, Shawn M. Rose, Nevin J. Varghese, Agastya D. Belur, Aditya Goyal, Joel M. Gelfand, Danielle A. Springer, Christopher K.E. Bleck, Crystal L. Thomas, Zu-Xi Yu, Mårten C.G. Winge, Howard S. Kruth, M. Peter Marinkovich, Aditya A. Joshi, Martin P. Playford, Nehal N. Mehta
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