Lavine K.J.,Center for Cardiovascular Research |
Epelman S.,Center for Cardiovascular Research |
Uchida K.,Center for Membrane Excitability |
Weber K.J.,Diabetic Cardiovascular Disease Center |
And 5 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2014
The mechanistic basis for why inflammation is simultaneously both deleterious and essential for tissue repair is not fully understood. Recently, a new paradigm has emerged: Organs are replete with resident macrophages of embryonic origin distinct from monocytederived macrophages. This added complexity raises the question of whether distinct immune cells drive inflammatory and reparative activities after injury. Previous work has demonstrated that the neonatal heart has a remarkable capacity for tissue repair compared with the adult heart, offering an ideal context to examine these concepts. We hypothesized that unrecognized differences in macrophage composition is a key determinant of cardiac tissue repair. Using a genetic model of cardiomyocyte ablation, we demonstrated that neonatal mice expand a population of embryonic-derived resident cardiac macrophages, which generate minimal inflammation and promote cardiac recovery through cardiomyocyte proliferation and angiogenesis. During homeostasis, the adult heart contains embryonic-derived macrophages with similar properties. However, after injury, these cells were replaced by monocyte-derived macrophages that are proinflammatory and lacked reparative activities. Inhibition of monocyte recruitment to the adult heart preserved embryonic-derived macrophage subsets, reduced inflammation, and enhanced tissue repair. These findings indicate that embryonicderived macrophages are key mediators of cardiac recovery and suggest that therapeutics targeting distinct macrophage lineages may serve as novel treatments for heart failure.
Houlind K.,Aarhus University Hospital |
Houlind K.,University of Southern Denmark |
Kjeldsen B.J.,University of Southern Denmark |
Madsen S.N.,Center for Cardiovascular Research |
And 4 more authors.
Circulation | Year: 2012
Background-Conventional coronary artery bypass grafting performed with the use of cardiopulmonary bypass is a well-validated treatment for patients with ischemic heart disease. Off-pump coronary artery bypass grafting (OPCAB) has been suggested to reduce the number of perioperative complications, especially in elderly patients. Methods and Results-In a multicenter, randomized trial, we assigned 900 patients >70 years of age to conventional coronary artery bypass grafting or OPCAB surgery. After 30 days, a blinded end-point committee assessed whether a combined end point of death, stroke, or myocardial infarction had occurred. At baseline and 6 months postoperatively, self-assessed quality of life was measured with the Medical Outcomes Study Short Form-36 and EuroQol-5D questionnaires. A 6-month follow-up of mortality was performed through the Danish National Registry. The proportion of patients experiencing the combined end point within 30 days was 10.2% for conventional coronary artery bypass grafting and 10.7% for OPCAB. Implied risk difference of 0.4% (with a 95% confidence interval,-3.6 to 4.4) showed nonsignificance in a standard test for equality (P=0.83) and for noninferiority with an inferiority margin of 0.5% (P=0.49). At the 6-month follow-up, mortality was 4.7% compared with 4.2% (P=0.75). Both groups showed significant improvement in self-assessed health-related quality of life. Conclusions-Both conventional coronary artery bypass grafting and OPCAB are safe procedures that improved the quality of life when performed in elderly patients. No major differences in intermediate-term outcomes were found. However, the noninferiority of OPCAB with the prespecified margin could not be confirmed. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00123981. © 2012 American Heart Association, Inc.
De Aguiar Vallim T.Q.,University of California at Los Angeles |
Tarling E.J.,University of California at Los Angeles |
Civelek M.,University of California at Los Angeles |
Baldan A.,Saint Louis University |
And 3 more authors.
Circulation Research | Year: 2013
RATIONALE:: The bile acid receptor farnesoid X receptor (FXR) regulates many aspects of lipid metabolism by variouscomplex and incompletely understood molecular mechanisms. We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism. OBJECTIVE:: To identify FXR-regulated microRNAs that were subsequently involved in regulating lipid metabolism. METHODS AND RESULTS:: ATP binding cassette transporter A1 (ABCA1) is a major determinant of plasma high-density lipoprotein (HDL)-cholesterol levels. Here, we show that activation of the nuclear receptor FXR in vivo increases hepatic levels of miR-144, which in turn lowers hepatic ABCA1 and plasma HDL levels. We identified 2 complementary sequences to miR-144 in the 3′ untranslated region of ABCA1 mRNA that are necessary for miR-144-dependent regulation. Overexpression of miR-144 in vitro decreased both cellular ABCA1 protein and cholesterol efflux to lipid-poor apolipoprotein A-I protein, whereas overexpression in vivo reduced hepatic ABCA1 protein and plasma HDL-cholesterol. Conversely, silencing miR-144 in mice increased hepatic ABCA1 protein and HDL-cholesterol. In addition, we used tissue-specific FXR-deficient mice to show that induction of miR-144 and FXR-dependent hypolipidemia requires hepatic, but not intestinal, FXR. Finally, we identified functional FXR response elements upstream of the miR-144 locus, consistent with direct FXR regulation. CONCLUSIONS:: We have identified a novel pathway involving FXR, miR-144, and ABCA1 that together regulate plasma HDL-cholesterol. © 2013 American Heart Association, Inc.
Von Websky K.,University of Potsdam |
Von Websky K.,Center for Cardiovascular Research |
Reichetzeder C.,University of Potsdam |
Reichetzeder C.,Center for Cardiovascular Research |
Hocher B.,University of Potsdam
Current Opinion in Nephrology and Hypertension | Year: 2014
PURPOSE OF REVIEW: Incretin-based therapy with glucagon-like peptide-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors is considered a promising therapeutic option for type 2 diabetes mellitus. Cumulative evidence, mainly from preclinical animal studies, reveals that incretin-based therapies also may elicit beneficial effects on kidney function. This review gives an overview of the physiology, pathophysiology, and pharmacology of the renal incretin system. RECENT FINDINGS: Activation of GLP-1R in the kidney leads to diuretic and natriuretic effects, possibly through direct actions on renal tubular cells and sodium transporters. Moreover, there is evidence that incretin-based therapy reduces albuminuria, glomerulosclerosis, oxidative stress, and fibrosis in the kidney, partially through GLP-1R-independent pathways. Molecular mechanisms by which incretins exert their renal effects are understood incompletely, thus further studies are needed. SUMMARY: The GLP-1R and DPP-4 are expressed in the kidney in various species. The kidney plays an important role in the excretion of incretin metabolites and most GLP-1R agonists and DPP-4 inhibitors, thus special attention is required when applying incretin-based therapy in renal impairment. Preclinical observations suggest direct renoprotective effects of incretin-based therapies in the setting of hypertension and other disorders of sodium retention, as well as in diabetic and nondiabetic nephropathy. Clinical studies are needed in order to confirm translational relevance from preclinical findings for treatment options of renal diseases. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.
Pries A.R.,Center for Cardiovascular Research |
Hopfner M.,Center for Cardiovascular Research |
Le Noble F.,Max Delbruck Centrum fur Molekulare Medizin |
Dewhirst M.W.,Duke University |
Secomb T.W.,University of Arizona
Nature Reviews Cancer | Year: 2010
Networks of blood vessels in normal and tumour tissues have heterogeneous structures, with widely varying blood flow pathway lengths. To achieve efficient blood flow distribution, mechanisms for the structural adaptation of vessel diameters must be able to inhibit the formation of functional shunts (whereby short pathways become enlarged and flow bypasses long pathways). Such adaptation requires information about tissue metabolic status to be communicated upstream to feeding vessels, through conducted responses. We propose that impaired vascular communication in tumour microvascular networks, leading to functional shunting, is a primary cause of dysfunctional microcirculation and local hypoxia in cancer. We suggest that anti-angiogenic treatment of tumours may restore vascular communication and thereby improve or normalize flow distribution in tumour vasculature. © 2010 Macmillan Publishers Limited. All rights reserved.
Carley A.N.,Center for Cardiovascular Research |
Taegtmeyer H.,University of Houston |
Lewandowski E.D.,Center for Cardiovascular Research
Circulation Research | Year: 2014
Metabolic signaling mechanisms are increasingly recognized to mediate the cellular response to alterations in workload demand, as a consequence of physiological and pathophysiological challenges. Thus, an understanding of the metabolic mechanisms coordinating activity in the cytosol with the energy-providing pathways in the mitochondrial matrix becomes critical for deepening our insights into the pathogenic changes that occur in the stressed cardiomyocyte. Processes that exchange both metabolic intermediates and cations between the cytosol and mitochondria enable transduction of dynamic changes in contractile state to the mitochondrial compartment of the cell. Disruption of such metabolic transduction pathways has severe consequences for the energetic support of contractile function in the heart and is implicated in the pathogenesis of heart failure. Deficiencies in metabolic reserve and impaired metabolic transduction in the cardiomyocyte can result from inherent deficiencies in metabolic phenotype or maladaptive changes in metabolic enzyme expression and regulation in the response to pathogenic stress. This review examines both current and emerging concepts of the functional linkage between the cytosol and the mitochondrial matrix with a specific focus on metabolic reserve and energetic efficiency. These principles of exchange and transport mechanisms across the mitochondrial membrane are reviewed for the failing heart from the perspectives of chronic pressure overload and diabetes mellitus. © 2014 American Heart Association, Inc.
Ebner N.,Applied Cachexia Research |
von Haehling S.,Applied Cachexia Research |
von Haehling S.,Center for Cardiovascular Research
Nutrients | Year: 2013
Iron is an element necessary for cells due to its capacity of transporting oxygen and electrons. One of the important co-morbidities in heart failure is iron deficiency. Iron has relevant biological functions, for example, the formation of haemoglobin, myoglobin and numerous enzymatic groups. The prevalence of iron deficiency increases with the severity of heart failure. For a long time, the influence of iron deficiency was underestimated especially in terms of worsening of cardiovascular diseases and of developing anaemia. In recent years, studies with intravenous iron agents in patients with iron deficiency and cardiovascular diseases indicated new insights in the improvement of therapy. Experimental studies support the understanding of iron metabolism. Many physicians remain doubtful of the use of intravenous iron due to reports of side effects. The aim of this review is to describe iron metabolism in humans, to highlight the influence of iron deficiency on the course and symptoms of heart failure, discuss diagnostic tools of iron deficiency and provide guidance on the use of intravenous iron. © 2013 by the authors; licensee MDPI, Basel, Switzerland.
Ostadalova I.,Center for Cardiovascular Research |
Ostadalova I.,Academy of Sciences of the Czech Republic
Physiological Research | Year: 2012
Selenium is a trace element that is essential for living organism. Its beneficial effect is, however, expressed in a very narrow dosage range: The high and low doses of selenium are connected with pathological manifestations. The toxicity depends on the chemical form of selenium, state of organism, interactions with heavy metals and on the stage of ontogenetic development. Whereas one dose of sodium selenite (20 μmol/kg b.w.) is lethal in adult rats, suckling rats are entirely resistant. However, within one week after administration of the same dose, cataract of eye lens developed. The highest incidence of cataract was observed in 10-day-old animals and it decreased until day 20. From postnatal day 20 to day 40 the rats were resistant to both the lethal and cataractogenic effects of selenium. The incidence of cataract may be suppressed by premature weaning, lower hydration of suckling, change of water soluble/water insoluble lens protein ratio, thyroxine treatment, and by interaction with mercury. By means of its oxidative and reduction properties, selenium is involved in the maintenance of the cell redox homeostasis. Typical example is its possible cardioprotective effect: Selenium decreased number of arrhythmias, reduced infarct size and improved the contractile recovery after ischemia/reperfusion injury. Selenium supplementation may thus increase cardiac tolerance to ischemic damage. © 2012 Institute of Physiology.
Lewandowski E.D.,Center for Cardiovascular Research
Circulation research | Year: 2013
Muscle carnitine palmitoyltransferase I is predominant in the heart, but the liver isoform (liver carnitine palmitoyltransferase I [L-CPT1]) is elevated in hearts with low long chain fatty acid oxidation, such as fetal and hypertrophied hearts. This work examined the effect of acute L-CPT1 expression on the regulation of palmitate oxidation and energy metabolism in intact functioning rat hearts for comparison with findings in hypertrophied hearts. L-CPT1 was expressed in vivo in rat hearts by coronary perfusion of Adv.cmv.L-CPT1 (L-CPT1, n=15) vs. phosphate-buffered saline (PBS) infusion (PBS, n=7) or empty virus (empty, n=5). L-CPT1 was elevated 5-fold at 72 hours after Adv.cmv.L-CPT1 infusion (P<0.05), but muscle carnitine palmitoyltransferase I was unaffected. Despite similar tricarboxylic acid cycle rates, palmitate oxidation rates were reduced with L-CPT1 (1.12 ± 0.29 μmol/min per gram of dry weight, mean±SE) vs. PBS (1.6 ± 0.34). Acetyl CoA production from palmitate was reduced with L-CPT1 (69 ± 0.02%; P<0.05; PBS=79 ± 0.01%; empty=81 ± 0.02%), similar to what occurs in hypertrophied hearts, and with no difference in malonyl CoA content. Glucose oxidation was elevated with L-CPT1 (by 60%). Surprisingly, L-CPT1 hearts contained elevated atrial natriuretic peptide, indicating induction of hypertrophic signaling. The results link L-CPT1 expression to reduced palmitate oxidation in a nondiseased adult heart, recapitulating the phenotype of reduced long chain fatty acid oxidation in cardiac hypertrophy. The implications are that L-CPT1 expression induces metabolic remodeling hypertrophic signaling and that regulatory factors beyond malonyl CoA in the heart regulate long chain fatty acid oxidation via L-CPT1.
Dragun D.,Center for Cardiovascular Research |
Catar R.,Center for Cardiovascular Research |
Philippe A.,Center for Cardiovascular Research
Current Opinion in Organ Transplantation | Year: 2013
Purpose of Review: Humoral responses beyond major histocompatibility antigens continue to receive the attention of the transplantation community. We report on clinical studies testing clinical relevance of non-human leukocyte antigen (HLA) antigens in solid organ transplantation and provide an update on novel experimental findings. A conceptual framework on the role of graft microenvironment during initiation of non-HLA-related humoral immunity is addressed as well. Recent Findings: Clinical relevance of antibodies targeting angiotensin type 1 receptor (AT1R-Abs) is broadly confirmed in renal and cardiac transplantation, where in addition antibodies against endothelin type A receptor (ETAR-Abs) were found. Obliterative lesions in lung allografts occur more commonly in the presence of antibodies directed against K-α 1 tubulin and collagen-V. Anti-perlecan antibodies are newly identified as accelerators of obliterative vascular lesions. Changes in the intragraft microenvironment, ischemia and alloimmunity seem to represent important permissive factors for non-HLA antibody responses. Summary: Confirmed clinical relevance of non-HLA humoral responses in solid organ transplantation emphasizes the need for revision of classical diagnostic approaches based solely on detection of HLA-donor-specific antibodies (DSA). A better understanding of intersections of HLA- and non-HLA-related mechanisms and identification of common effector mechanisms would represent an important step towards targeted therapies. © 2013 Wolters Kluwer Health | Lippincott Williams & Wilkins.