Pathological hypertrophy reverses β2-adrenergic receptor-induced angiogenesis in mouse heart (original) (raw)
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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.
…, 2006
Cardiac hypertrophy is associated with upregulation of vascular endothelial growth factor (VEGF) in the myocardium. Here, we evaluated the effects of a decoy VEGF receptor on heart morphology and function to a murine model of pressure overload hypertrophy. Mice were administered adenoviral vector encoding a decoy VEGF receptor (Ad-Flk), and their hearts were subjected to pressure overload by transverse aortic constriction (TAC). Treatment with Ad-Flk led to a net reduction in capillary density in hearts subjected to TAC. Ad-Flk also led to a reduction in TAC-induced cardiac hypertrophy and promoted left ventricle dilatation and a loss in contractile function. Treatment with Ad-Flk markedly increased myocardial fibrosis and collagen gene upregulation. In contrast, Ad-Flk had no effect on any of these parameters in sham-treated mice. Administration of a VEGF trap reagent diminished pressure overload cardiac hypertrophy and promoted the progression to heart failure but had no effect on sham-treated animals. These findings suggest that VEGF is required to maintain myocardial capillary density and that reductions in the vascular bed are associated with the transition from compensatory hypertrophy to failure. (Hypertension. 2006;47:887-893.
Cardiovascular Research, 2007
Aim The regulation of angiogenesis in the hypertrophied overloaded heart is incompletely understood. Bone-marrow-derived progenitor cells have been shown to contribute to endothelial homeostasis, repair, and new blood vessel formation. We therefore studied the effects of pressure overload on angiogenesis and progenitor cells. Methods and results Pressure overload induced by transaortic constriction (TAC, C57/Bl6 mice, 360 mm for 35 days) increased left ventricular (LV) systolic pressure, the ratio of heart weight to tibia length, cardiomyocyte diameters, and cardiac apoptosis and fibrosis compared to sham-operated mice. In the TAC group, the number of cycling Ki67 pos cells increased from none to 0.1 + 0.02% in cardiomyocytes and from 0.17 + 0.02% to 0.65 + 0.1% in non-cardiomyocytes, P , 0.001. stem cell antigen 1 pos /vascular endothelial growth factor receptor 2 pos endothelial progenitor cells (EPC) increased to 210 + 25% in the blood and to 196 + 21% in the bone marrow (P , 0.01). TAC upregulated cultured spleen-derived DiLDL pos /lectin pos EPC to 221 + 37%, P , 0.001. Cardiac hypertrophy and upregulation of EPC secondary to cardiac pressure overload were associated with increased extra-cardiac neoangiogenesis (54 + 12% increase, P , 0.05). In endothelial nitric oxide synthase double knockout mice, the upregulation of EPC by TAC was abolished. Maladaptive myocardial remodelling in TAC mice was characterized by a reduction of CD31 pos cells. In mice transplanted with green fluorescent protein pos bone marrow, TAC markedly increased myocardial bone marrow-derived CD31 pos cells from 2.37 + 0.4% to 7.76 + 1.5% and MEF2 pos cells from 1.8 + 0.4/mm 2 to 20.5 + 5.3/mm 2 , P , 0.05. Conclusion Pressure-induced myocardial hypertrophy leads to upregulation of systemic EPCs, increased extra-cardiac angiogenesis, and upregulation of intra-myocardial bone marrow-derived endothelial and myocyte precursor cells. The data show that afterload-dependent regulation of bone marrow-derived progenitor cells contributes to angiogenesis in myocardial hypertrophy.
American Journal of Physiology-Heart and Circulatory Physiology, 2009
This study utilized a transgenic mouse model that expresses an inducible dominant-negative mutation of the transforming growth factor (TGF)-β type II receptor (DnTGFβRII) to define the structural and functional responses of the left ventricle (LV) to pressure-overload stress in the absence of an intact TGF-β signaling cascade. DnTGFβRII and nontransgenic (NTG) control mice (male, 8–10 wk) were randomized to receive Zn2+ (25 mM ZnSO4 in drinking H2O to induce DnTGFβRII gene expression) or control tap H2O and then further randomized to undergo transverse aortic constriction (TAC) or sham surgery. At 7 days post-TAC, interstitial nonmyocyte proliferation (Ki67 staining) was greatly reduced in LV of DnTGFβRII+Zn2+ mice compared with the other TAC groups. At 28 and 120 days post-TAC, collagen deposition (picrosirius-red staining) in LV was attenuated in DnTGFβRII+Zn2+ mice compared with the other TAC groups. LV end systolic diameter and end systolic and end diastolic volumes were markedl...
Scientific Reports, 2020
Animal models of pressure overload are valuable for understanding hypertensive heart disease. We characterised a surgical model of pressure overload-induced hypertrophy in C57BL/6J mice produced by suprarenal aortic constriction (SAC). Compared to sham controls, at one week post-SAC systolic blood pressure was significantly elevated and left ventricular (LV) hypertrophy was evident by a 50% increase in the LV weight-to-tibia length ratio due to cardiomyocyte hypertrophy. As a result, LV end-diastolic wall thickness-to-chamber radius (h/R) ratio increased, consistent with the development of concentric hypertrophy. LV wall thickening was not sufficient to normalise LV wall stress, which also increased, resulting in LV systolic dysfunction with reductions in ejection fraction and fractional shortening, but no evidence of heart failure. Pathological LV remodelling was evident by the re-expression of fetal genes and coronary artery perivascular fibrosis, with ischaemia indicated by enhanced cardiomyocyte Hif1a expression. The expression of stem cell factor receptor, c-Kit, was low basally in cardiomyocytes and did not change following the development of robust hypertrophy, suggesting there is no role for cardiomyocyte c-Kit signalling in pathological LV remodelling following pressure overload. Heart failure is a common end-result of a variety of cardiovascular diseases, including ischaemic and hypertensive heart disease. Hypertension is the primary cause of pathological left ventricular (LV) hypertrophy in 75% of patients 1. While the hypertrophic response is initially compensatory to maintain heart function in the face of pressure overload (PO), pathological hypertrophy eventually becomes decompensatory, with decreased cardiac performance that precedes overt heart failure. Current treatments for heart failure merely slow the progression to end-stage heart failure, since there is no cure other than heart transplantation. Animal models of hypertensive heart disease are, thus, critical to developing potential new regenerative therapies 2. Two commonly used cardiac injury models are myocardial infarction (MI) produced by ligation of the left anterior descending coronary artery, and aortic constriction; the latter first developed and characterised by Rytand 3 and Goldblatt et al. 4 , produced by ligating the descending abdominal aorta between or immediately above the renal arteries. Constriction of the abdominal aorta induces PO leading to the rapid development of cardiac hypertrophy and heart failure 2,5. Historically, aortic constriction models were developed in larger animal species, including rabbits, dogs, guinea pigs and rats 2,5 , but over the last few decades these techniques have been adapted to mice-the preferred species for genetic studies that are also economical 6,7. Thoracic aortic constriction
Circulation, 2000
Background —Transgenic mice with constitutive myocardium-targeted expression of a peptide inhibitor of the β-adrenergic receptor kinase (βARKct) have increased in vivo cardiac function and enhanced β-adrenergic receptor (βAR) responsiveness. Methods and Results —In the present study, we created transgenic mice with myocardium-targeted βARKct transgene expression under control of the CARP (cardiac ankyrin repeat protein) promoter, which is active during cardiac development and inactive in the normal adult mouse heart. Consistent with this, adult CARP-βARKct transgenic mice have normal in vivo cardiac contractility and βAR responsiveness indistinguishable from their nontransgenic littermates (NLCs). However, because CARP is in a group of fetal genes activated in the adult ventricle during hypertrophy, we subjected animals to transverse aortic constriction (TAC) to induce pressure overload. Seven days after TAC, CARP-βARKct hearts had elevations in left ventricular mass similar to thos...
CCN2/CTGF attenuates myocardial hypertrophy and cardiac dysfunction upon chronic pressure-overload
International Journal of Cardiology, 2013
Background: Myocardial CCN2/CTGF (connective tissue growth factor) is strongly induced in heart failure (HF) and acts as a cardioprotective factor in ischemia/reperfusion injury. However, its functional role in myocardial hypertrophy remains unresolved. Methods and results: Transgenic mice with cardiac-restricted overexpression of CTGF (Tg-CTGF) and non-transgenic littermate control (NLC) mice were subjected to chronic pressure-overload by abdominal aortic banding. After 4 weeks of persistent pressure-overload, a time point at which compensatory hypertrophy of the left ventricle (LV) prevails, Tg-CTGF mice displayed diminished increase of LV mass compared with NLC. At study end-point after 12 weeks of sustained aortic constriction, the mice displayed LV dilatation and reduced cardiac function. Repeated transthoracic echocardiography during the 12 weeks of chronic pressure-overload, revealed attenuation of LV dilatation and virtually sustained systolic function in Tg-CTGF mice compared with NLC mice. Also, increase of LV mass was blunted in Tg-CTGF versus NLC mice at study end-point. Consistently, increases of myocardial ANP, BNP and skeletal α-actin mRNA levels were blunted in Tg-CTGF mice subjected to chronic pressure-overload. Furthermore, cardiac myocytes from Tg-CTGF mice displayed increased phospho-NFATc2 levels and attenuated hypertrophic response upon stimulation with α 1 -adrenoceptor agonist, indicating that CTGF attenuates hypertrophic signaling in cardiac myocytes. Increase of myocardial collagen contents in mice subjected to aortic banding was similar in Tg-CTGF and NLC mice, indicating that CTGF have minimal impact on myocardial collagen deposition. Conclusion: This study provides novel evidence that CTGF attenuates cardiac hypertrophy upon chronic pressure-overload due to inhibition of signaling mechanisms that promote pathologic myocardial hypertrophy.
AJP: Heart and Circulatory Physiology, 2010
Inhibition of transforming growth factor- signaling induces left ventricular dilation and dysfunction in the pressure-overloaded heart. This study utilized a transgenic mouse model that expresses an inducible dominant-negative mutation of the transforming growth factor (TGF)- type II receptor (DnTGFRII) to define the structural and functional responses of the left ventricle (LV) to pressure-overload stress in the absence of an intact TGF- signaling cascade. DnTGFRII and nontransgenic (NTG) control mice (male, 8 -10 wk) were randomized to receive Zn 2ϩ (25 mM ZnSO4 in drinking H 2O to induce DnTGFRII gene expression) or control tap H2O and then further randomized to undergo transverse aortic constriction (TAC) or sham surgery. At 7 days post-TAC, interstitial nonmyocyte proliferation (Ki67 staining) was greatly reduced in LV of DnTGFRIIϩZn 2ϩ mice compared with the other TAC groups. At 28 and 120 days post-TAC, collagen deposition (picrosirius-red staining) in LV was attenuated in DnTGFRIIϩZn 2ϩ mice compared with the other TAC groups. LV end systolic diameter and end systolic and end diastolic volumes were markedly increased, while ejection fraction and fractional shortening were significantly decreased in TAC-DnTGFRIIϩZn 2ϩ mice compared with the other groups at 120 days post-TAC. These data indicate that interruption of TGF- signaling attenuates pressure-overload-induced interstitial nonmyocyte proliferation and collagen deposition and promotes LV dilation and dysfunction in the pressure-overloaded heart, thus creating a novel model of dilated cardiomyopathy. cardiac hypertrophy; Smad protein; myofibroblast; extracellular matrix
Histochemistry and Cell Biology, 2009
Myocardial fibrosis is an integral component of most cardiac pathologic conditions and contributes to the development of both systolic and diastolic dysfunction. Because of the availability of genetically manipulated animals, mouse models are essential for understanding the mechanisms involved in the pathogenesis of cardiac fibrosis. Accordingly, we characterized the inflammatory and fibrotic response in a mouse model of cardiac pressure overload due to transverse aortic constriction (TAC). Following TAC, mouse hearts exhibited induction of chemokines and proinflammatory cytokines, associated with macrophage, but not neutrophil, infiltration. Induction of inflammatory cytokines was followed by a late upregulation of transforming growth factor (TGF)-β isoforms, activation of the Smad2/3 and Smad1/5 pathways, induction of matricellular proteins, and deposition of collagen. Inflammatory activity decreased after 28 days of TAC; at this timepoint established fibrosis was noted, accompanied by ventricular dilation and systolic dysfunction. Late induction of inhibitory mediators, such as TGF-β, may play an essential role in the transition from inflammation to fibrosis by suppressing inflammatory gene synthesis while inducing matrix deposition. Our findings identify molecular mediators and pathways with a potential role in cardiac fibrosis laying the foundations for studies exploring the pathogenesis of fibrotic cardiac remodeling using genetically targeted mice.