Journal: Cardiovascular Research

Abbreviation

Cardiovasc Res

Publisher

Oxford University Press

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ISSN

1755-3245
0008-6363

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Publications 1 - 10 of 11
  • Short-term delivery of anti-PlGF antibody delays progression of atherosclerotic plaques to vulnerable lesions
    Item type: Journal Article
    Roncal, Carmen; Buysschaert, Ian; Gerdes, Norbert; et al. (2010)
    Cardiovascular Research
  • Cardiac-specific BACH1 ablation attenuates pathological cardiac hypertrophy by inhibiting the Ang II type 1 receptor expression and the Ca2+/CaMKII pathway
    Item type: Journal Article
    Wei, Xiangxiang; Jin, Jiayu; Wu, Jian; et al. (2023)
    Cardiovascular Research
    Aims: BACH1 is up-regulated in hypertrophic hearts, but its function in cardiac hypertrophy remains largely unknown. This research investigates the function and mechanisms of BACH1 in the regulation of cardiac hypertrophy. Methods and results: Male cardiac-specific BACH1 knockout mice or cardiac-specific BACH1 transgenic (BACH1-Tg) mice and their respective wild-type littermates developed cardiac hypertrophy induced by angiotensin II (Ang II) or transverse aortic constriction (TAC). Cardiac-specific BACH1 knockout in mice protected the hearts against Ang II- and TAC-induced cardiac hypertrophy and fibrosis, and preserved cardiac function. Conversely, cardiac-specific BACH1 overexpression markedly exaggerated cardiac hypertrophy and fibrosis and reduced cardiac function in mice with Ang II- and TAC-induced hypertrophy. Mechanistically, BACH1 silencing attenuated Ang II- and norepinephrine-stimulated calcium/calmodulin-dependent protein kinase II (CaMKII) signalling, the expression of hypertrophic genes, and hypertrophic growth of cardiomyocytes. Ang II stimulation promoted the nuclear localization of BACH1, facilitated the recruitment of BACH1 to the Ang II type 1 receptor (AT1R) gene promoter, and then increased the expression of AT1R. Inhibition of BACH1 attenuated Ang II-stimulated AT1R expression, cytosolic Ca2+ levels, and CaMKII activation in cardiomyocytes, whereas overexpression of BACH1 led to the opposite effects. The increased expression of hypertrophic genes induced by BACH1 overexpression upon Ang II stimulation was suppressed by CaMKII inhibitor KN93. The AT1R antagonist, losartan, significantly attenuated BACH1-mediated CaMKII activation and cardiomyocyte hypertrophy under Ang II stimulation in vitro. Similarly, Ang II-induced myocardial pathological hypertrophy, cardiac fibrosis, and dysfunction in BACH1-Tg mice were blunted by treatment with losartan. Conclusion: This study elucidates a novel important role of BACH1 in pathological cardiac hypertrophy by regulating the AT1R expression and the Ca2+/CaMKII pathway, and highlights potential therapeutic target in pathological cardiac hypertrophy.
  • Cellular engineering of ventricular adult rat cardiomyocytes
    Item type: Journal Article
    Weikert, Christian; Eppenberger-Eberhardt, Monika; Eppenberger, Hans M. (2003)
    Cardiovascular Research
  • Identification of pulmonary artery stiffening due to left heart disease by ultrasonography
    Item type: Journal Article
    Kucherenko, Mariya M.; Kukucka, Marian; Sang, Pengchao; et al. (2025)
    Cardiovascular Research
    Aims Pulmonary hypertension (PH) is a common complication of left heart disease (LHD) that leads to right heart failure and death. Pulmonary artery (PA) stiffening has recently emerged as an important diagnostic and prognostic parameter in PH. The present study aimed to develop and validate an ultrasonographic index to identify PA stiffening in PH due to LHD. Methods and results First, ultrasonographic stiffness index (US-SI) was derived from pulmonary arterial (PA) radial strain (PA-RS), diameter, and stroke volume in rat model and correlated with ex vivo measured ‘true’ PA stiffness E. Then, US-SI was validated in a cohort of 24 LHD patients with or without PH prior to heart transplantation and again compared with ‘true’ PA stiffness measured ex vivo in collected PA specimens. In rats, ultrasonographic PA-RS and US-SI correlated closely with E, and both were able to detect ‘true’ PA stiffening with ≥80% sensitivity and specificity. In LHD patients, even though ultrasonographic right PA radial strain or US-SI correlated similarly with E, observer assessment and testing for diagnostic validity identified US-SI as more robust and accurate method that detects ‘true’ PA stiffening with 83.3% sensitivity and 95.8% specificity. Conclusions Both PA strain and US-SI allow for ultrasonographic detection of PA stiffening in patients or animal models with LHD; however, US-SI identifies patients with stiffened PA with higher diagnostic validity and accuracy.
  • Celiprolol but not losartan improves the biomechanical integrity of the aorta in a mouse model of vascular Ehlers-Danlos syndrome
    Item type: Journal Article
    Dubacher, Nicolo; Münger, Justyna; Gorosabel, Maria C.; et al. (2020)
    Cardiovascular Research
    Aims Antihypertensive drugs are included in the medical therapy of vascular Ehlers–Danlos syndrome (vEDS). The β-blocker celiprolol has been suggested to prevent arterial damage in vEDS, but the underlying mechanism remains unclear. It is also unknown whether the widely used angiotensin II receptor type 1 antagonist losartan has a therapeutic effect in vEDS. Here, we evaluated the impact of celiprolol and losartan on the biomechanical integrity of the vEDS thoracic aorta. Methods and results We established a new approach to measure the maximum tensile force at rupture of uniaxially stretched murine thoracic aortic rings. In a vEDS model, which we (re-)characterized here at molecular level, heterozygous mice showed a significant reduction in the rupture force compared to wild-type mice, reflecting the increased mortality due to aortic rupture. For the assessment of treatment effects, heterozygous mice at 4 weeks of age underwent a 4-week treatment with celiprolol, losartan, and, as a proof-of-concept drug, the matrix metalloproteinase inhibitor doxycycline. Compared to age- and sex-matched untreated heterozygous mice, treatment with doxycycline or celiprolol resulted in a significant increase of rupture force, whereas no significant change was detected upon losartan treatment. Conclusions In a vEDS model, celiprolol or doxycycline, but not losartan, can improve the biomechanical integrity of the aortic wall, thereby potentially reducing the risk of dissection and rupture. As doxycycline is a broad-spectrum antibiotic with considerable side effects, celiprolol may be more suitable for a long-term therapy and thus rather indicated for the medication of patients with vEDS.
  • Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation
    Item type: Journal Article
    Trachet, Bram; Fraga-Silva, Rodrigo A.; Piersigilli, Alessandra; et al. (2015)
    Cardiovascular Research
  • Short-term preoperative protein restriction attenuates vein graft disease via induction of cystathionine γ-lyase
    Item type: Journal Article
    Trocha, Kaspar M; Kip, Peter; Tao, Ming; et al. (2020)
    Cardiovascular Research
    Aims Therapies to prevent vein graft disease, a major problem in cardiovascular and lower extremity bypass surgeries, are currently lacking. Short-term preoperative protein restriction holds promise as an effective preconditioning method against surgical stress in rodent models, but whether it can improve vein graft patency after bypass surgery is undetermined. Here, we hypothesized that short-term protein restriction would limit vein graft disease via up-regulation of cystathionine γ-lyase and increased endogenous production of the cytoprotective gaseous signalling molecule hydrogen sulfide. Methods and results Low-density lipoprotein receptor knockout mice were preconditioned for 1 week on a high-fat high-cholesterol (HFHC) diet with or without protein prior to left common carotid interposition vein graft surgery with caval veins from donor mice on corresponding diets. Both groups were returned to a complete HFHC diet post-operatively, and vein grafts analysed 4 or 28 days later. A novel global transgenic cystathionine γ-lyase overexpressing mouse model was also employed to study effects of genetic overexpression on graft patency. Protein restriction decreased vein graft intimal/media+adventitia area and thickness ratios and intimal smooth muscle cell infiltration 28 days post-operatively, and neutrophil transmigration 4 days post-operatively. Protein restriction increased cystathionine γ-lyase protein expression in aortic and caval vein endothelial cells (ECs) and frequency of lung EC producing hydrogen sulfide. The cystathionine γ-lyase inhibitor propargylglycine abrogated protein restriction-mediated protection from graft failure and the increase in hydrogen sulfide-producing ECs, while cystathionine γ-lyase transgenic mice displayed increased hydrogen sulfide production capacity and were protected from vein graft disease independent of diet. Conclusion One week of protein restriction attenuates vein graft disease via increased cystathionine γ-lyase expression and hydrogen sulfide production, and decreased early inflammation. Dietary or pharmacological interventions to increase cystathionine γ-lyase or hydrogen sulfide may thus serve as new and practical strategies to improve vein graft durability.
  • Endothelial dysfunction in COVID-19: a position paper of the ESC Working Group for Atherosclerosis and Vascular Biology, and the ESC Council of Basic Cardiovascular Science
    Item type: Journal Article
    Evans, Paul C.; Rainger, G. Ed; Mason, Justin C.; et al. (2020)
    Cardiovascular Research
    The COVID-19 pandemic is an unprecedented healthcare emergency causing mortality and illness across the world. Although primarily affecting the lungs, the SARS-CoV-2 virus also affects the cardiovascular system. In addition to cardiac effects, e.g. myocarditis, arrhythmias, and myocardial damage, the vasculature is affected in COVID-19, both directly by the SARS-CoV-2 virus, and indirectly as a result of a systemic inflammatory cytokine storm. This includes the role of the vascular endothelium in the recruitment of inflammatory leucocytes where they contribute to tissue damage and cytokine release, which are key drivers of acute respiratory distress syndrome (ARDS), in disseminated intravascular coagulation, and cardiovascular complications in COVID-19. There is also evidence linking endothelial cells (ECs) to SARS-CoV-2 infection including: (i) the expression and function of its receptor angiotensin-converting enzyme 2 (ACE2) in the vasculature; (ii) the prevalence of a Kawasaki disease-like syndrome (vasculitis) in COVID-19; and (iii) evidence of EC infection with SARS-CoV-2 in patients with fatal COVID-19. Here, the Working Group on Atherosclerosis and Vascular Biology together with the Council of Basic Cardiovascular Science of the European Society of Cardiology provide a Position Statement on the importance of the endothelium in the underlying pathophysiology behind the clinical presentation in COVID-19 and identify key questions for future research to address. We propose that endothelial biomarkers and tests of function (e.g. flow-mediated dilatation) should be evaluated for their usefulness in the risk stratification of COVID-19 patients. A better understanding of the effects of SARS-CoV-2 on endothelial biology in both the micro- and macrovasculature is required, and endothelial function testing should be considered in the follow-up of convalescent COVID-19 patients for early detection of long-term cardiovascular complications.
  • Angiotensin II infusion into ApoE(-/-) mice: a model for aortic dissection rather than abdominal aortic aneurysm?
    Item type: Journal Article
    Trachet, Bram; Aslanidou, Lydia; Piersigilli, Alessandra; et al. (2017)
    Cardiovascular Research
    Aims Angiotensin II-infused ApoE(-/-) mice are a popular mouse model for preclinical aneurysm research. Here, we provide insight in the often-reported but seldom-explained variability in shape of dissecting aneurysms in these mice. Methods and results N = 45 excised aortas were scanned ex vivo with phase-contrast X-ray tomographic microscopy. Micro-ruptures were detected near the ostium of celiac and mesenteric arteries in 8/11 mice that were sacrificed after 3 days of angiotensin II-infusion. At later time points (after 10, 18, and 28 days) the variability in shape of thoraco-abdominal lesions (occurring in 31/34 mice) was classified into 7 different categories based on the presence or absence of a medial tear (31/31), an intramural hematoma (23/31) or a false channel (11/23). Medial tears were detected both in the thoracic and the abdominal aorta and were most prevalent at the left and ventral aspects of celiac and mesenteric arteries. The axial length of the hematoma strongly correlated to the total number of ruptured branch ostia (r2 = 0.78) and in 22/23 mice with a hematoma the ostium of the left suprarenal artery had ruptured. Supraceliac diameters at baseline were significantly lower for mice that did not develop an intramural hematoma, and the formation of a false channel within that intramural hematoma depended on the location, rather than the length, of the medial tear. Conclusion Based on our observations we propose an elaborate hypothesis that explains how aortic side branches (i) affect the initiation and propagation of medial tears and the subsequent adventitial dissection and (ii) affect the variability in shape of dissecting aneurysms. This hypothesis was partially validated through the live visualization of a dissecting aneurysm that formed during micro-CT imaging, and led us to the conclusion that angiotensin II-infused mice are more clinically relevant for the study of aortic dissections than for the study of abdominal aortic aneurysms.
  • Deletion of fibroblast activation protein provides atheroprotection
    Item type: Journal Article
    Stein, Sokrates; Weber, Julien; Nusser-Stein, Stefanie; et al. (2021)
    Cardiovascular Research
    Aims Fibroblast activation protein (FAP) is upregulated at sites of tissue remodelling including chronic arthritis, solid tumours, and fibrotic hearts. It has also been associated with human coronary atherosclerotic plaques. Yet, the causal role of FAP in atherosclerosis remains unknown. To investigate the cause–effect relationship of endogenous FAP in atherogenesis, we assessed the effects of constitutive Fap deletion on plaque formation in atherosclerosis-prone apolipoprotein E (Apoe) or low-density lipoprotein receptor (Ldlr) knockout mice. Methods and results Using en face analyses of thoraco-abdominal aortae and aortic sinus cross-sections, we demonstrate that Fap deficiency decreased plaque formation in two atherosclerotic mouse models (−46% in Apoe and −34% in Ldlr knockout mice). As a surrogate of plaque vulnerability fibrous cap thickness was used; it was increased in Fap-deficient mice, whereas Sirius red staining demonstrated that total collagen content remained unchanged. Using polarized light, atherosclerotic lesions from Fap-deficient mice displayed increased FAP targets in terms of enhanced collagen birefringence in plaques and increased pre-COL3A1 expression in aortic lysates. Analyses of the Stockholm Atherosclerosis Gene Expression data revealed that FAP expression was increased in human atherosclerotic compared to non-atherosclerotic arteries. Conclusions Our data provide causal evidence that constitutive Fap deletion decreases progression of experimental atherosclerosis and increases features of plaque stability with decreased collagen breakdown. Thus, inhibition of FAP expression or activity may not only represent a promising therapeutic target in atherosclerosis but appears safe at the experimental level for FAP-targeted cancer therapies.
Publications 1 - 10 of 11