b 2 -Adrenergic Receptor Overexpression Exacerbates Development of Heart Failure After Aortic Stenosis (original) (raw)
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2-Adrenergic Receptor Overexpression Exacerbates Development of Heart Failure After Aortic Stenosis
Circulation, 2000
Background--Adrenergic signaling is downregulated in the failing heart, and the significance of such change remains unclear. Methods and Results-To address the role of -adrenergic dysfunction in heart failure (HF), aortic stenosis (AS) was induced in wild-type (WT) and transgenic (TG) mice with cardiac targeted overexpression of  2 -adrenergic receptors (ARs), and animals were studied 9 weeks later. The extents of increase in systolic arterial pressure (PϽ0.01 versus controls), left ventricular (LV) hypertrophy (TG, 94Ϯ6 to 175Ϯ7 mg; WT, 110Ϯ6 to 168Ϯ10 mg; both PϽ0.01), and expression of ANP mRNA were similar between TG and WT mice with AS. TG mice had higher incidences of premature death and critical illness due to heart failure (75% versus 23%), pleural effusion (81% versus 45%), and left atrial thrombosis (81% versus 36%, all PϽ0.05). A more extensive focal fibrosis was found in the hypertrophied LV of TG mice (PϽ0.05). These findings indicate a more severe LV dysfunction in TG mice. In sham-operated mice, LV dP/dt max and heart rate were markedly higher in TG than WT mice (both PϽ0.01). dP/dt max was lower in both AS groups than in sham-operated controls, and this tended to be more pronounced in TG than WT mice (Ϫ32Ϯ5% versus Ϫ16Ϯ6%, Pϭ0.059), although dP/dt max remained higher in TG than WT groups (PϽ0.05).
British Journal of Pharmacology, 2008
Background and purpose: The role of b-adrenoceptors in heart disease remains controversial. Although b-blockers ameliorate the progression of heart disease, the mechanism remains undefined. We investigated the effect of b-adrenoceptors on cardiac hypertrophic growth using b 1 -and b 2 -adrenoreceptor knockout and wild-type (WT) mice. Experimental approach: Mice were subjected to aortic banding or sham surgery, and their cardiac function was determined by echocardiography and micromanometry. Key results: At 4 and 12 weeks after aortic banding, the left ventricle:body mass ratio was increased by 80-87% in wild-type mice, but only by 15% in knockouts, relative to sham-operated groups. Despite the blunted hypertrophic growth, ventricular function in knockouts was maintained. WT mice responded to pressure overload with up-regulation of gene expression of inflammatory cytokines and fibrogenic growth factors, and with severe cardiac fibrosis. All these effects were absent in the knockout animals. Conclusion and implications: Our findings of a markedly attenuated cardiac hypertrophy and fibrosis following pressure overload in this knockout model emphasize that b-adrenoceptor signalling plays a central role in cardiac hypertrophy and maladaptation following pressure overload.
Journal of Molecular and Cellular Cardiology, 2009
Stimulation of the β-adrenergic system is important in the pathological response to sustained cardiac stress, forming the rationale for the use of β-blockers in heart failure. The β3-adrenoreceptor (AR) is thought to couple to the inhibitory G-protein, G i , with downstream signaling through nitric oxide, although its role in the heart remains controversial. In this study, we tested whether lack of β3-AR influences the myocardial response to pressure-overload. Baseline echocardiography in mice lacking β3-AR (β3 −/− ) compared to wild type (WT) showed mild LV hypertrophy at 8 weeks that worsened as they aged. β3 −/− mice had much greater mortality after transverse aortic constriction (TAC) than WT controls. By 3 weeks of TAC, systolic function was worse. After 9 weeks of TAC, β3 −/− mice also had greater LV dilation, myocyte hypertrophy and enhanced fibrosis. NOS activity declined in β3 −/− -TAC hearts after 9 weeks, and total and NOS-dependent superoxide rose, indicating heightened oxidative stress and NOS uncoupling. The level of eNOS phosphorylation in β3 −/− -TAC hearts was diminished, and nNOS and iNOS expression levels were increased. GTP cyclohydrolase-1 expression was reduced, although total BH4 levels were not depleted. 3 weeks of BH4 treatment rescued β3 −/− mice from worsened remodeling after TAC, and lowered NOS-dependent superoxide. Thus, lack of β3-AR signaling exacerbates cardiac pressure-overload induced remodeling and enhances NOS uncoupling and consequent oxidant stress, all of which can be rescued with exogenous BH4. These data suggest a cardioprotective role for the β3-AR in modulating oxidative stress and adverse remodeling in the failing heart.
Cardiac hypertrophy is enhanced in PPAR -/- mice in response to chronic pressure overload
Cardiovascular Research, 2008
Time for primary review: 37 days Aims Peroxisome proliferator-activated receptor-a (PPARa) is a nuclear receptor regulating cardiac metabolism that also has anti-inflammatory properties. Since the activation of inflammatory signalling pathways is considered to be important in cardiac hypertrophy and fibrosis, it is anticipated that PPARa modulates cardiac remodelling. Accordingly, in this study the hypothesis was tested that the absence of PPARa aggravates the cardiac hypertrophic response to pressure overload. Methods and results Male PPARa2/2 and wild-type mice were subjected to transverse aortic constriction (TAC) for 28 days. TAC resulted in a more pronounced increase in ventricular weight and left ventricular (LV) wall thickness in PPARa2/2 than in wild-type mice. Compared with sham-operated mice, TAC did not affect cardiac function in wild-type mice, but significantly depressed LV ejection fraction and LV contractility in PPARa2/2 mice. Moreover, after TAC mRNA levels of hypertrophic (atrial natriuretic factor, a-skeletal actin), fibrotic (collagen 1, matrix metalloproteinase-2), and inflammatory (interleukin-6, tumour necrosis factor-a, cyclo-oxygenase-2) marker genes were higher in PPARa2/2 than in wild-type mice. The mRNA levels of genes involved in fatty acid metabolism (long-chain acyl-CoA synthetase, hydroxyacyl-CoA dehydrogenase) were decreased in PPARa2/2 mice, but were not further compromised by TAC. Conclusion The present findings show that the absence of PPARa results in a more pronounced hypertrophic growth response and cardiac dysfunction that are associated with an enhanced expression of markers of inflammation and extracellular matrix remodelling. These findings indicate that PPARa exerts salutary effects during cardiac hypertrophy.
PLoS ONE, 2012
Adenosine binds to three G protein-coupled receptors (R) located on the cardiomyocyte (A 1 -R, A 2A -R and A 3 -R) and provides cardiac protection during both ischemic and load-induced stress. While the role of adenosine receptor-subtypes has been well defined in the setting of ischemia-reperfusion, far less is known regarding their roles in protecting the heart during other forms of cardiac stress. Because of its ability to increase cardiac contractility and heart rate, we hypothesized that enhanced signaling through A 2A -R would protect the heart during the stress of transverse aortic constriction (TAC). Using a cardiac-specific and inducible promoter, we selectively over-expressed A 2A -R in FVB mice. Echocardiograms were obtained at baseline, 2, 4, 8, 12, 14 weeks and hearts were harvested at 14 weeks, when WT mice developed a significant decrease in cardiac function, an increase in end systolic and diastolic dimensions, a higher heart weight to body weight ratio (HW/BW), and marked fibrosis when compared with sham-operated WT. More importantly, these changes were significantly attenuated by over expression of the A 2A -R. Furthermore, WT mice also demonstrated marked increases in the hypertrophic genes b-myosin heavy chain (b-MHC), and atrial natriuretic factor (ANF) -changes that are mediated by activation of the transcription factor GATA-4. Levels of the mRNAs encoding b-MHC, ANP, and GATA-4 were significantly lower in myocardium from A 2A -R TG mice after TAC when compared with WT and sham-operated controls. In addition, three inflammatory factors genes encoding cysteine dioxygenase, complement component 3, and serine peptidase inhibitor, member 3N, were enhanced in WT TAC mice, but their expression was suppressed in A 2A -R TG mice. A 2A -R over-expression is protective against pressure-induced heart failure secondary to TAC. These cardioprotective effects are associated with attenuation of GATA-4 expression and inflammatory factors. The A 2A -R may provide a novel new target for pharmacologic therapy in patients with cardiovascular disease. Citation: Hamad EA, Zhu W, Chan TO, Myers V, Gao E, et al. (2012) Cardioprotection of Controlled and Cardiac-Specific Over-Expression of A 2A -Adenosine Receptor in the Pressure Overload. PLoS ONE 7(7): e39919.
Cardioprotective Effect of Beta-3 Adrenergic Receptor Agonism
Journal of the American College of Cardiology, 2012
The aim of this study was to determine whether activation of 3-adrenergic receptor (AR) and downstream signaling of nitric oxide synthase (NOS) isoforms protects the heart from failure and hypertrophy induced by pressure overload.
Pfl�gers Archiv European Journal of Physiology, 2003
Controversy exists whether the development of left-ventricular hypertrophy (LVH) is a mechanism able to prevent cardiac dysfunction under conditions of pressure overload. In the present study we re-assessed the long-term effects of attenuating LVH by using l-and d-propranolol, which are equally able to inhibit the development of LVH induced by aortic banding. The aortic arch was banded proximal to the left common carotid artery in 71 CD-1 mice that were then assigned randomly to receive l-propranolol, d-propranolol (both 80 mg/kg per day) or vehicle. Concurrently, shamoperated mice were given l-propranolol, d-propranolol or vehicle. LV dimension and performance were evaluated under isoflurane anaesthesia by cine-magnetic resonance imaging, echocardiography and cardiac cathe-G. Marano ( ) ) · S. Palazzesi · S. Gaudi tibial length · LVWS: left-ventricular wall stress · MR(I): magnetic resonance (imaging) · PS: left-ventricular peak systolic pressure · PWT D : posterior wall thickness (diastolic) · PWT S : posterior wall thickness (systolic) · SWT D : end-diastolic septal thickness · SV: stroke volume · TL: tibial length · WS: wall stress
Pathological hypertrophy reverses β2-adrenergic receptor-induced angiogenesis in mouse heart
Physiological reports, 2015
β-adrenergic activation and angiogenesis are pivotal for myocardial function but the link between both events remains unclear. The aim of this study was to explore the cardiac angiogenesis profile in a mouse model with cardiomyocyte-restricted overexpression of β2-adrenoceptors (β2-TG), and the effect of cardiac pressure overload. β2-TG mice had heightened cardiac angiogenesis, which was essential for maintenance of the hypercontractile phenotype seen in this model. Relative to controls, cardiomyocytes of β2-TGs showed upregulated expression of vascular endothelial growth factor (VEGF), heightened phosphorylation of cAMP-responsive-element-binding protein (CREB), and increased recruitment of phospho-CREB, CREB-binding protein (CBP), and p300 to the VEGF promoter. However, when hearts were subjected to pressure overload by transverse aortic constriction (TAC), angiogenic signaling in β2-TGs was inhibited within 1 week after TAC. β2-TG hearts, but not controls, exposed to pressure ove...
Regression of pressure overload-induced left ventricular hypertrophy in mice
AJP: Heart and Circulatory Physiology, 2005
As a prelude to investigating the mechanism of regression of pressure overload-induced left ventricular (LV) hypertrophy (LVH), we studied the time course for the development and subsequent regression of LVH as well as accompanying alterations in cardiac function, histology, and gene expression. Mice were subjected to aortic banding for 4 or 8 wk to establish LVH, and regression was initiated by release of aortic banding for 6 wk. Progressive increase in LV mass and gradual chamber dilatation and dysfunction occurred after aortic banding. LVH was also associated with myocyte enlargement, interstitial fibrosis, and enhanced expression of atrial natriuretic peptide, collagen I, collagen III, and matrix metalloproteinase-2 but suppressed expression of α-myosin heavy chain and sarcoplasmic reticulum Ca2+-ATPase. Aortic debanding completely or partially reversed LVH, chamber dilatation and dysfunction, myocyte size, interstitial fibrosis, and gene expression pattern, each with a distinct...
Journal of Biological Chemistry, 2001
α 1 -adrenergic receptors (α 1A , α 1B , α 1D ) are the primary regulators of sympathetic control over systemic arterial blood pressure and blood flow. While the vasoconstrictory action of the α 1A and α 1D subtypes is thought to be mainly responsible for this activity, the role of the α 1B adrenergic receptor (α 1B AR) in this process is controversial. This is due, in part, to a lack of agonists and antagonists that possess adequate α 1B -selectivity. To alleviate this limitation and to examine the cardiovascular activities of the α 1B AR, we have generated transgenic mice engineered to over-express either wild-type or constitutively active α 1B ARs. Transgenic receptor expression was under the control of the isogenic promoter, thus assuring appropriate developmental and tissue specific expression. Cardiovascular phenotypes displayed by transgenic mice included early stage myocardial hypertrophy and hypotension under both basal and stressed conditions. Indicative of cardiac hypertrophy, transgenic mice displayed an increased heart to body weight ratio that was confirmed by the echocardiographic finding of increased interventricular septum and posterior wall thicknesses. Functional deficits included an increased isovolumetric relaxation time, a decreased heart rate and a decreased cardiac output.