Abstract:
AIMS:Angiotensin II is a potential contributor to the development of abdominal aortic aneurysm (AAA). In aortic vascular smooth muscle cells, exposure to angiotensin II induces mitochondrial fission via dynamin-related protein 1 (Drp1). However, pathophysiological relevance of mitochondrial morphology in angiotensin II-associated AAA remains unexplored. Here, we tested the hypothesis that mitochondrial fission is involved in the development of AAA. METHODS AND RESULTS:Immunohistochemistry was performed on human AAA samples and revealed enhanced expression of Drp1. In C57BL6 mice treated with angiotensin II plus β-aminopropionitrile, AAA tissue also showed an increase in Drp1 expression. A mitochondrial fission inhibitor, mdivi1, attenuated AAA size, associated aortic pathology, Drp1 protein induction and mitochondrial fission but not hypertension in these mice. Moreover, Western blot analysis showed that induction of matrix metalloproteinase-2, which precedes the development of AAA, was blocked by mdivi1. Mdivi1 also reduced the development of AAA in apolipoprotein E deficient mice infused with angiotensin II. As with mdivi1, Drp1+/- mice treated with angiotensin II plus β-aminopropionitrile showed a decrease in AAA compared to control Drp1+/+ mice. In abdominal aortic vascular smooth muscle cells, angiotensin II induced phosphorylation of Drp1 and mitochondrial fission, the latter of which was attenuated with Drp1 silencing as well as mdivi1. Angiotensin II also induced vascular cell adhesion molecule-1 expression and enhanced leukocyte adhesion and mitochondrial oxygen consumption in smooth muscle cells, which were attenuated with mdivi1. CONCLUSION:These data indicate that Drp1 and mitochondrial fission play salient roles in AAA development, which likely involves mitochondrial dysfunction and inflammatory activation of vascular smooth muscle cells. TRANSLATIONAL PERSPECTIVES:Mitochondrial fission/fusion regulation is critical to maintain mitochondrial homeostasis. A shift toward mitochondrial fission is associated with a variety of cardiovascular diseases. A GTPase, Drp1 is known to mediate mitochondrial fission and we found evidence of Drp1 dysregulation in human and mouse abdominal aortic aneurysms (AAA). The results from the present study demonstrate that pharmacological as well as genetic inhibition of mitochondrial fission via Drp1 prevents AAA formation and vascular smooth muscle aneurysmal phenotype in mouse models of the disease. These data indicate that intervening in this pathway may have therapeutic potential for treating AAA.
journal_name
Cardiovasc Resjournal_title
Cardiovascular researchauthors
Cooper HA,Cicalese S,Preston KJ,Kawai T,Okuno K,Choi ET,Kasahara S,Uchida HA,Otaka N,Scalia R,Rizzo V,Eguchi Sdoi
10.1093/cvr/cvaa133subject
Has Abstractpub_date
2020-05-08 00:00:00eissn
0008-6363issn
1755-3245pii
5834715pub_type
杂志文章abstract::The QT interval, a global index of ventricular repolarization, varies among individuals and is influenced by diverse physiologic and pathophysiologic stimuli such as gender, age, heart rate, electrolyte concentrations, concomitant cardiac disease, and other diseases such as diabetes. Many drugs produce a small but rep...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvz013
更新日期:2019-04-15 00:00:00
abstract:OBJECTIVE:To examine whether altered PCO2 or HCO3- at normal pH potentiate agonist-induced vasoconstriction of small pulmonary arteries, and if so to determine the mechanism. METHODS:Small intrapulmonary arteries (IPA) from rats were mounted on a myograph and PGF2alpha (3 microM)-induced tension recorded before and 40...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2004.10.038
更新日期:2005-02-01 00:00:00
abstract:OBJECTIVE:Polymorphonuclear leukocytes (PMN), retained in the microvascular bed, can contribute to postischemic myocardial reperfusion injury. Since a beneficial effect of ACE-inhibition on reperfusion injury has been reported, we investigated the impact of cilazaprilat on PMN dependent reperfusion injury in isolated g...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00191-0
更新日期:1997-12-01 00:00:00
abstract:OBJECTIVE:The aim was to examine the ventricular expression of brain natriuretic peptide (BNP) in the transplanted human heart. METHODS:Serial right ventricular biopsies (n = 68) and plasma samples (n = 68) were obtained for measurement of BNP and atrial natriuretic peptide (ANP) from 14 orthotopic cardiac transplant ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/27.2.188
更新日期:1993-02-01 00:00:00
abstract:OBJECTIVES:To investigate the effect of alpha,beta(1) and beta(2) adrenergic receptor (AR) stimulation on coronary hemodynamics, myocardial oxygen consumption (M(v)O(2)) and metabolic substrate preference in advanced dilated cardiomyopathy (DCM). METHODS:We studied 19 conscious, instrumented dogs with pacing-induced D...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(01)00490-4
更新日期:2002-02-01 00:00:00
abstract:OBJECTIVE:This study aimed to examine the effects of adenovirus-mediated expression of p35, a baculovirus gene, on apoptosis induced by hypoxia/reoxygenation (H/R) in cardiomyocytes. METHODS:Neonatal rat cardiomyocytes were infected with recombinant adenoviral vectors expressing p35 (Ad2/CMVp35) or no transgene (Ad2/C...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(02)00412-1
更新日期:2002-08-01 00:00:00
abstract:AIMS:Nonsense mutations in the SCN5A gene result in truncated, non-functional derivatives of the cardiac Na+ channel and thus cause arrhythmias. Studies of other genes suggest that pathogenic phenotypes of nonsense mutations may be alleviated by enhancing readthrough, which enables ribosomes to ignore premature termina...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvp116
更新日期:2009-08-01 00:00:00
abstract:AIMS:Crosstalk between cardiomyocytes and fibroblasts in physiological conditions and during disease remains poorly defined. Previous studies have shown that fibroblasts and myocytes interact via paracrine communication, but several experimental confounding factors, including the use of immature myocytes and the induct...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvu264
更新日期:2015-03-01 00:00:00
abstract::Since data on velocity fields in the ascending aorta downstream of normal aortic valves in pigs have not yet been obtained velocity profiles were visualised using a hot film anemometer needle probe before and after total cardiopulmonary bypass and cold cardioplegic arrest. Furthermore, measurements were made during in...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/22.7.464
更新日期:1988-07-01 00:00:00
abstract::The afterload dependency of relaxation rate was reappraised in isolated canine hearts both in isovolumic and isobaric contractions by using the reliable exponential method in which the asymptote LV pressure (P chi) is variable. This method provided a closer correlation (r = 0.999 +/- 0.001) between the measured LV pre...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/19.10.649
更新日期:1985-10-01 00:00:00
abstract::Data from experiments in isolated cardiac muscle preparations indicate that adenosine in high concentration (10(-3) mol X litre-1) exerts a negative inotropic effect on the myocardium under basal conditions. The following study was performed to test the hypothesis that adenosine exerts a similar negative inotropic eff...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/18.4.220
更新日期:1984-04-01 00:00:00
abstract:AIMS:A cytosolic calcium (Ca(2+)(i)) increase is an important activation signal for the endothelium. We investigated whether interendothelial spreading of the Ca(2+) signal via gap junctions (GJs) plays a role for the overall Ca(2+)(i) increase in response to vasoactive agonists. METHODS AND RESULTS:In human umbilical...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvr345
更新日期:2012-03-01 00:00:00
abstract:OBJECTIVE:To determine the role of calcineurin and Src tyrosine kinase in the regulation of inducible nitric oxide synthase (iNOS) expression and protection in cardiomyocytes. METHODS:iNOS expression was studied in isolated neonatal rat ventricular myocyte cultures in response to bacterial lipopolysaccharide (LPS) or ...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2006.05.026
更新日期:2006-09-01 00:00:00
abstract::Physical training has been advocated to minimize the problems associated with coronary heart disease; however, the responsible mechanisms are obscure. Rats trained to run on a treadmill were subjected to acute conditions of hypoxia and myocardial ischaemia. Trained rats were better able to maintain a higher level of c...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/10.3.359
更新日期:1976-05-01 00:00:00
abstract:STUDY OBJECTIVE:The aim of the study was to examine, in a whole heart preparation, the relationship between length changes in cardiac muscle and tension development and length dependent activation. DESIGN:Rat hearts were perfused by the Langendorff technique and isovolumetric pressure changes in the left ventricle, pr...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/24.3.254
更新日期:1990-03-01 00:00:00
abstract:OBJECTIVE:The purpose of this study was to assess whether the plasma levels of soluble adhesion molecules including E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) are elevated in patients with variant angina and whether they are released in the coronary circulation...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00143-0
更新日期:1997-10-01 00:00:00
abstract:AIMS:Therapeutic use of sulfhydrylated inhibitor S-zofenopril has raised different hypotheses regarding the role played by its thiol group in the beneficial clinical effects exerted compared with other angiotensin-converting enzyme (ACE) inhibitors. Here, we investigated hydrogen sulfide (H2S) pathway as accountable fo...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvu026
更新日期:2014-04-01 00:00:00
abstract::One of the striking differences that distinguish the adult from the embryonic heart in mammals and set it apart from the heart in urodeles and teleosts is the incapacity of cardiomyocytes to respond to damage by proliferation. While the molecular reasons underlying these characteristics still await elucidation, mounti...
journal_title:Cardiovascular research
pub_type: 杂志文章,评审
doi:10.1093/cvr/cvu057
更新日期:2014-05-01 00:00:00
abstract:AIMS:AMP-activated protein kinase (AMPK) is thought to be a central player in regulating myocardial metabolism and its activation has been shown to inhibit cardiac hypertrophy. Recently, mice with muscle-specific deletion of AMPK β1/β2 subunits (AMPKβ1β2-deficient mice, β1β2M-KO) have been generated and possess <10% of...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvv166
更新日期:2015-07-15 00:00:00
abstract::Injudicious selection of a saphenous vein graft can adversely affect the the late postoperative patency of the proximal coronary artery which it bypasses. The purpose of this investigation was to deduce an upper bound for graft diameter, at small angle of distal anastomosis, below which the stenosed artery will remain...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/13.7.370
更新日期:1979-07-01 00:00:00
abstract:OBJECTIVES:Injury stimulates smooth muscle cell (SMC) migration and proliferation by mechanisms that are incompletely understood. Surgical preparative injury is an important determinant of neointimal thickening in human saphenous vein bypass grafts. We investigate here whether basement-membrane-degrading metalloprotein...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(96)00211-8
更新日期:1997-02-01 00:00:00
abstract:OBJECTIVE:Recently, we have found that rat CMV (RCMV) infected smooth muscle cells (SMCs) in rat carotid arteries when administered 14 days after balloon injury. In the present study we investigated (1) the long term effects of CMV infection on neointimal cross-sectional area, and (2) whether the phenotype of the intim...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(97)00189-2
更新日期:1997-11-01 00:00:00
abstract:AIMS:The heart contains c-kit(+) progenitors that maintain cardiac homeostasis. Cardiac c-kit(+) cells are multipotent and give rise to myocardial, endothelial and smooth muscle cells, both in vitro and in vivo. C-kit(+) cells have been thoroughly investigated for their stem cell activity, susceptibility to stress cond...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/cvq292
更新日期:2011-02-01 00:00:00
abstract::Segments of saphenous vein from patients undergoing coronary artery by-pass graft surgery were frozen in liquid nitrogen immediately on dissection (control), after stripping of the adventitia and side branch ligation (manipulation), after distention with blood (distention), or at completion of the last proximal anasto...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/19.6.326
更新日期:1985-06-01 00:00:00
abstract:OBJECTIVES:Action potential prolongation related to the alteration of several membrane currents is constantly reported in heart failure (HF) but reports about its role in arrhythmogenesis are sparse. Our aim was to determine, by analogy with long QT syndromes, whether prolonged repolarization is associated with increas...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(02)00236-5
更新日期:2002-04-01 00:00:00
abstract:OBJECTIVE:The potential use of bone marrow stromal cells (MSCs) as a cellular therapy for chronic cardiac diseases relies on the ability of the cell to replicate extensively in vitro and to give rise to myogenic cells that can replace the damaged cardiomyocytes. For this reason the present study investigated the replic...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(03)00265-7
更新日期:2003-05-01 00:00:00
abstract:OBJECTIVE:We have previously demonstrated that nuclear factor kappa B (NFkappaB) activation is needed for the development of cardiac hypertrophy in vivo. NFkappaB is a downstream transcription factor in the Toll-like receptor (TLR)-mediated signaling pathway; therefore, we investigated a role of TLR4 in cardiac hypertr...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/j.cardiores.2005.05.025
更新日期:2005-11-01 00:00:00
abstract:OBJECTIVE:To assess the contribution of the Na, K pump current (I(p)) to the action potential duration (APD) and effective refractory period (ERP) in human atrial cells, and to investigate whether I(p) contributes to the changes in APD and ERP associated with chronic atrial fibrillation (AF). METHODS:Action potentials...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(03)00466-8
更新日期:2003-09-01 00:00:00
abstract::Pulsatile haemodynamics associated with graded degrees of experimentally produced stenosis were studied in the canine femoral artery. Invasively determined pulsatile blood flow and noninvasively determined blood velocity with Doppler ultrasound were measured an average of 1.3 and 2.3 cm proximal to the stenosis, respe...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1093/cvr/13.1.45
更新日期:1979-01-01 00:00:00
abstract:OBJECTIVE:Macrophage migration inhibitory factor (MIF), which plays a pivotal role in the control of inflammatory responses, was first characterized as a T-cell cytokine, but later was also found as a pituitary peptide released in response to infection and stress. However, MIF's role and expression in the myocardium ha...
journal_title:Cardiovascular research
pub_type: 杂志文章
doi:10.1016/s0008-6363(01)00408-4
更新日期:2001-12-01 00:00:00