Abstract 1769: Caveolin-1 Regulates TGF-Beta Signaling in Cardiac Remodeling

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Shelley Miyasato ◽  
Oana Bollt ◽  
Joyce Pike ◽  
Ann Hashimoto ◽  
Ralph V Shohet ◽  
...  
Keyword(s):  
Inflammatory Response ◽  
Ventricular Function ◽  
Cardiac Remodeling ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Fibrous Tissue ◽  
Left Ventricular ◽  
Caveolin 1 ◽  
Post Surgery ◽  
Smad2 Phosphorylation

In cardiac fibrosis, fibrous tissue replaces healthy contractile tissue. The regulation of these processes is controlled in large part by transforming growth factor-β (TGF-β). Caveolin-1 (cav1) regulates TGF-β signaling by either sequestering the TGF-β receptor complex or enhancing its degradation. Thus, cav1 may prevent TGF-β directed fibrosis. To investigate the role of cav1 in cardiac remodeling, we performed left ventricular cryoinjury in Cav1-deficient (Cav1−/−) mice and wild-type controls. Ventricular function was followed by echocardiography, and 3, 14, and 30 days after surgery, cardiac RNA and protein were analyzed for inflammatory responses, connective tissue and TGF-β signaling related proteins. Cryoinjured WT presented reduced cav1 expression. Concurrently, evidence of activation of TGF-β signaling was measured as shown by increase of Smad2 phosphorylation. Moreover Cav1−/− cryoinjured hearts had enhanced Smad2 phosphorylation. Collagen gene expression was transiently upregulated in cryoinjured WT mice 3 days post surgery (2.5-fold) and this elevation persisted in Cav1−/− hearts (3.5-fold at 14 days). The level of collagenases (mmp-8 and -13) expression was dramatically increased in the 3-day cryoinjured WT but not in Cav1−/− mice. As a result, augmented collagen deposition, resulting from increased collagen expression and reduced degradation by collagenases, was observed by Masson’s trichrome and picrosirius staining in injured Cav1−/− hearts. WT mice had a transient decline in fractional shortening (FS) but function returned to baseline by 30 days post-injury. In contrast, cryoinjured Cav1−/− mice had a significant lower % FS after 30 days compared to baseline or to cryoinjured WT (67.4 ± 9.6, 76 ± 11, 76.9 ± 5.5, respectively). Moreover Cav1−/− mice presented an altered inflammatory response following cryoinjury. Reduced macrophage infiltrates and IL-6 level of expression were also measured in cryoinjured Cav1−/− mice. These data indicate that in absence of caveolae, TGF-β signaling is enhanced, and this leads to a disordered inflammatory response and suboptimal cardiac remodeling that may impair left ventricular function.

GIP advanced cardiac remodeling after LAD ligation leading to improved left-ventricular function

2018 ◽  
Author(s):  
A Dieckerhoff ◽  
J Möllmann ◽  
M Schwarz ◽  
E Liehn ◽  
S Diebold ◽  
...  
Keyword(s):  
Left Ventricular Function ◽  
Ventricular Function ◽  
Cardiac Remodeling ◽  
Left Ventricular

Abstract 14664: Reduced Activin Like Kinase 1 Activity Promotes Cardiac Fibrosis in Heart Failure

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Kevin Morine ◽  
Vikram Paruchuri ◽  
Xiaoying Qiao ◽  
Emily Mackey ◽  
Mark Aronovitz ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Remodeling ◽  
Cardiac Fibrosis ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Left Ventricular ◽  
Lv Function ◽  
Type I ◽  
Mrna Levels ◽  
Protein Levels

Introduction: Activin receptor like kinase 1 (ALK1) mediates signaling via transforming growth factor beta-1 (TGFb1), a pro-fibrogenic cytokine. No studies have defined a role for ALK1 in heart failure. We tested the hypothesis that reduced ALK1 expression promotes maladaptive cardiac remodeling in heart failure. Methods and Results: ALK1 mRNA expression was quantified by RT-PCR in left ventricular (LV) tissue from patients with end-stage heart failure and compared to control LV tissue obtained from the National Disease Research Interchange (n=8/group). Compared to controls, LV ALK1 mRNA levels were reduced by 85% in patients with heart failure. Next, using an siRNA approach, we tested whether reduced ALK1 levels promote TGFb1-mediated collagen production in human cardiac fibroblasts. Treatment with an ALK1 siRNA reduced ALK1 mRNA levels by 75%. Compared to control, TGFb1-mediated Type I collagen and pSmad-3 protein levels were 2.5-fold and 1.7-fold higher, respectively, after ALK1 depletion. To explore a role for ALK1 in heart failure, ALK1 haploinsufficient (ALK1) and wild-type mice (WT; n=8/group) were studied 2 weeks after thoracic aortic constriction (TAC). Compared to WT, baseline LV ALK1 mRNA levels were 50% lower in ALK1 mice. Both LV and lung weights were higher in ALK1 mice after TAC. Cardiomyocyte area and LV mRNA levels of BNP, RCAN, and b-MHC were increased similarly, while SERCa levels were reduced in both ALK1 and WT mice after TAC. Compared to WT, LV fibrosis (Figure) and Type 1 Collagen mRNA and protein levels were higher among ALK1 mice. Compared to WT, LV fractional shortening (48±12 vs 26±10%, p=0.01) and survival (Figure) were lower in ALK1 mice after TAC. Conclusions: Reduced LV expression of ALK1 is associated with advanced heart failure in humans and promotes early mortality, impaired LV function, and cardiac fibrosis in a murine model of heart failure. Further studies examining the role of ALK1 and ALK1 inhibitors on cardiac remodeling are required.

Adipolin/CTRP12 protects against pathological vascular remodelling through suppression of smooth muscle cell growth and macrophage inflammatory response

2019 ◽  
Vol 116 (1) ◽  
pp. 237-249 ◽  
Author(s):  
Hayato Ogawa ◽  
Koji Ohashi ◽  
Masanori Ito ◽  
Rei Shibata ◽  
Noriyoshi Kanemura ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Growth Factor ◽  
Inflammatory Response ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Transforming Growth Factor Β ◽  
Vascular Remodelling ◽  
Vsmc Proliferation ◽  
Protein Levels ◽  
Β Receptor

AbstractAimsSecreted factors produced by adipose tissue are involved in the pathogenesis of cardiovascular disease. We previously identified adipolin, also known as C1q/TNF-related protein 12, as an insulin-sensitizing adipokine. However, the role of adipolin in vascular disease remains unknown. Here, we investigated whether adipolin modulates pathological vascular remodelling.Methods and resultsAdipolin-knockout (APL-KO) and wild-type (WT) mice were subjected to wire-induced injury of the femoral artery. APL-KO mice showed increased neointimal thickening after vascular injury compared with WT mice, which was accompanied by an enhanced inflammatory response and vascular cell proliferation in injured arteries. Adipolin deficiency also led to a reduction in transforming growth factor-β (TGF-β) 1 protein levels in injured arteries. Treatment of cultured macrophages with adipolin protein led to a reduction in lipopolysaccharide-stimulated expression of inflammatory mediators, including tumour necrosis factor (TNF)-α, interleukin (IL) 6, and monocyte chemotactic protein (MCP)-1. These effects were reversed by inhibition of TGF-β receptor II (TGF-βRII)/Smad2 signalling. Adipolin also reduced platelet-derived growth factor (PDGF)-BB-stimulated proliferation of vascular smooth muscle cells (VSMCs) through a TGF-βRII/Smad2-dependent pathway. Furthermore, adipolin treatment significantly increased TGF-β1 concentration in media from cultured VSMCs and macrophages.ConclusionThese data indicate that adipolin protects against the development of pathological vascular remodelling by attenuating macrophage inflammatory responses and VSMC proliferation.

Optimal timing of the Ross procedure in the management of chronic aortic incompetence in the young

2003 ◽  
Vol 13 (3) ◽  
pp. 253-257 ◽  
Author(s):  
Michael M. H. Cheung ◽  
Ian D. Sullivan ◽  
Marc R. de Leval ◽  
Victor T. Tsang ◽  
Andrew N. Redington
Keyword(s):  
Left Ventricular Function ◽  
Ventricular Function ◽  
Contractile Function ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Optimal Timing ◽  
Ross Procedure ◽  
Z Score ◽  
Post Surgery ◽  
Aortic Incompetence

The appropriate timing of intervention in patients with chronic aortic incompetence allows recovery of ventricular function. We sought to determine the optimal timing of the Ross procedure for chronic aortic incompetence in young patients. We retrospectively analysed case notes, and measured pre- and postoperative echocardiographic indexes of left ventricular function, in patients who had undergone the Ross procedure for chronic aortic incompetence. Methods and results: We found 21 patients with preoperative and postoperative data suitable for analysis. Their age at operation ranged from 5.6 to 26 years, with a median of 13.8 years, and the duration of follow-up was from 0.5 to 6.8 years, with a median of 2.4 years. The preoperative left ventricular end-diastolic dimension was converted to a z-score, and this was used as a threshold to divide the population. Using the threshold of a preoperative left ventricular z-score of more than 3 to divide the population did not show any difference in postoperative parameters of left ventricular function. Significant differences were found postoperatively, however, in both the left ventricular z-score and the ratio of left ventricular end-diastolic radius to posterior wall thickness in diastole, with a cutoff preoperative threshold z-score greater than 4. Conclusion: The increase in the ratio of left ventricular end-diastolic radius to the thickness of the posterior wall in diastole would suggest that there is disruption of left ventricular short axis architecture and myocardial contractile function when intervention is postponed. The significantly larger left ventricular dimension at end-diastole, despite the reduction in volume loading post surgery, may also demonstrate irreversible structural changes. Our data would suggest that recovery of left ventricular function is less likely when the left ventricular z-score has reached the value of 4, and that, ideally, intervention should be performed when the z-score approaches or exceeds 3.

scholarly journals Phenotypic Switching in Cryptococcus neoformans Contributes to Virulence by Changing the Immunological Host Response

2008 ◽  
Vol 76 (9) ◽  
pp. 4322-4331 ◽  
Author(s):  
Abraham Guerrero ◽  
Bettina C. Fries
Keyword(s):  
Inflammatory Response ◽  
Cryptococcus Neoformans ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Inflammatory Responses ◽  
Interleukin 10 ◽  
Host Responses ◽  
Phenotypic Switching ◽  
Wild Type ◽  
Necrosis Factor Alpha

ABSTRACT Cryptococcus neoformans is an encapsulated opportunistic organism that can undergo phenotypic switching. In this process, the parent smooth colony (SM) switches to a more virulent mucoid colony (MC) variant. The host responses mounted against the SM and MC variants differ, and lower tissue interleukin 10 (IL-10) levels are consistently observed in lungs of MC-infected C57BL/6 and BALB/c mice. This suggested different roles of this cytokine in SM and MC infections. The objective of this study was to compare survival rates and characterize the host responses of SM- and MC-infected IL-10-depleted (IL-10−/−) mice, which exhibit a Th1-polarized immune response and are considered resistant hosts. As expected, SM-infected IL-10−/− mice survived longer than wild-type mice, whereas MC-infected IL-10−/− mice did not exhibit a survival benefit. Consistent with this observation, we demonstrated marked differences in the inflammatory responses of SM- and MC-infected IL-10−/− and wild-type mice. This included a more Th1-polarized inflammatory response with enhanced recruitment of macrophages and natural killer and CD8 cells in MC- than in SM-infected IL-10−/− and wild-type mice. In contrast, both SM-infected IL-10−/− and wild-type mice exhibited higher recruitment of CD4 cells, consistent with enhanced survival and differences in recruitment and Th1/Th2 polarization. Lung tissue levels of IL-21, IL-6, IL-4, transforming growth factor beta, IL-12, and gamma interferon were higher in MC-infected IL-10−/− and wild-type mice than in SM-infected mice, whereas tumor necrosis factor alpha levels were higher in SM-infected IL-10−/− mice. In conclusion, the MC variant elicits an excessive inflammatory response in a Th1-polarized host environment, and therefore, the outcome is negatively affected by the absence of IL-10.

scholarly journals Cardiomyopathy in young adults with classic mitral valve prolapse

2013 ◽  
Vol 24 (4) ◽  
pp. 694-701 ◽  
Author(s):  
Eduard Malev ◽  
Svetlana Reeva ◽  
Lyubov Vasina ◽  
Eugeny Timofeev ◽  
Asiyet Pshepiy ◽  
...  
Keyword(s):  
Young Adults ◽  
Growth Factor ◽  
Mitral Valve ◽  
Left Ventricular Function ◽  
Ventricular Function ◽  
Mitral Valve Prolapse ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Left Ventricular ◽  
Control Group

AbstractBackground: In some inherited connective tissue diseases with involvement of the cardiovascular system, for example, Marfan syndrome, early impairment of left ventricular function, which have been described as Marfan-related cardiomyopathy has been reported. Our aim was to evaluate the left ventricular function in young adults with mitral valve prolapse without significant mitral regurgitation using two-dimensional strain imaging and to determine the possible role of the transforming growth factor-β pathway in its deterioration. Methods: We studied 78 young adults with mitral valve prolapse without mitral regurgitation in comparison with 80 sex-matched and age-matched healthy individuals. Longitudinal strain and strain rates were defined using spackle tracking. Concentrations of transforming growth factor-β1 and β2 in serum were determined by enzyme-linked immunosorbent assays. Results: In 29 patients, classic relapse was identified with a leaflet thickness of ≥ 5 mm; 49 patients had a non-classic mitral valve prolapse. Despite the similar global systolic function, a significant reduction in global strain was found in the classic group (−15.5 ± 2.9%) compared with the non-classic group (−18.7 ± 3.8; p = 0.0002) and the control group (−19.6 ± 3.4%; p < 0.0001). In young adults with non-classic prolapse, a reduction in longitudinal deformation was detected only in septal segments. Transforming growth factor-β1 and β2 serum levels were elevated in patients with classic prolapse as compared with the control group and the non-classic mitral valve prolapse group. Conclusions: These changes in the deformations may be the first signs of deterioration of the left ventricular function and the existence of primary cardiomyopathy in young adults with mitral valve prolapse, which may be caused by increased transforming growth factor-β signalling.

Sign in / Sign up

Export Citation Format

Share Document