Acute and specific collagen type I degradation increases diastolic and developed tension in perfused rat papillary muscle

2004 ◽  
Vol 286 (3) ◽  
pp. H889-H894 ◽  
Author(s):  
Regis R. Lamberts ◽  
Maurice J. J. M. F. Willemsen ◽  
Néstor G. Pérez ◽  
Pieter Sipkema ◽  
Nico Westerhof

Collagen degradation is suggested to be responsible for long-term contractile dysfunction in different cardiomyopathies, but the effects of acute and specific collagen type I removal (main type in the heart muscle) on tension have not been studied. We determined the diastolic and developed tension length relations in isometric contracting perfused rat papillary muscles (perfusion pressure 60 cmH2O) before and after acute and specific removal of small collagen struts with the use of purified collagenase type I. At 95% of the maximal length (95% Lmax), diastolic tension increased 20.4 ± 8.1% ( P < 0.05, n = 6) and developed tension increased 15.0 ± 6.7% after collagenase treatment compared with time controls. Treatment increased the diastolic muscle diameter by 7.1 ± 3.4% at 95% Lmax, whereas the change in diameter due to contraction was not changed. Diastolic coronary flow and normalized coronary arterial flow impediment did not change after collagenase treatment. Electron microscopy revealed that the number of small collagen struts, interconnecting myocytes, and capillaries was reduced to ∼32% after treatment. We conclude that removal of the small collagen struts by acute and specific collagen type I degradation increases diastolic and developed tension in perfused papillary muscle. We suggest that diastolic tension is increased due to edema, whereas developed tension is increased because the removal of the struts poses a lower lateral load on the cardiac myocytes, allowing more myocyte thickening.

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Begoña Lopez-Salazar ◽  
Alfonso Macias ◽  
Juan Jose Gavira ◽  
Javier Diez-Martinez ◽  
Ignacio Garcia-Bolao

We investigated whether modification of collagen type I turnover is related to the long-term response to cardiac resynchronization therapy (CRT). Methods and Results: Serum carboxy-terminal propeptide of procollagen type I or PICP (a marker of collagen type I synthesis), carboxy-terminal telopeptide of collagen type I or CITP (a marker of collagen type I degradation), matrix metalloproteinase (MMP)-1, -2, -9 and tissue inhibitor of MMP (TIMP)-1, were measured in 54 patients (35 responders) at baseline and after 1 year of CRT. At baseline, PICP and the ratio PICP: CITP were higher (p < 0.01) in responders than in nonresponders. At 1-year, both PICP (p < 0.005) and the ratio PICP:CITP (p < 0.05) decreased in responders, while increased in nonresponders (p < 0.005 and p < 0.05, respectively). MMP-1 (p < 0.05), MMP-9 (p < 0.005), and the ratio MMP-1:TIMP-1 (p < 0.01) increased, while TIMP-1 decreased (p < 0.005) in responders, but remained unchanged in nonresponders. The ratio PICP:CITP correlated inversely with ejection fraction (r = -0.501, p < 0.01) and directly with left ventricular end-diastolic diameter (r = 0.376, p < 0.05) in responders after CRT. Direct correlations were found between MMP-1, and -9 and ejection fraction (r = 0.315, p < 0.05, r = 0.516, p < 0.01) in responders after CRT. Conclusions The ability of CRT to modify collagen type I turnover (i.e. decreasing synthesis and increasing degradation) is associated with its long-term response.


2016 ◽  
Vol 32 ◽  
pp. 138-148 ◽  
Author(s):  
Mihyun Lee ◽  
Youngjin Kim ◽  
Ji Hyun Ryu ◽  
Kyuri Kim ◽  
Yong-Mahn Han ◽  
...  

2018 ◽  
Vol 315 (4) ◽  
pp. H802-H813 ◽  
Author(s):  
Guohua Li ◽  
Wenjuan Xing ◽  
Min Zhang ◽  
Fenghao Geng ◽  
Hongyan Yang ◽  
...  

Diabetic cardiac fibrosis increases ventricular stiffness and facilitates the occurrence of diastolic dysfunction. Our previous studies have shown that berberine, a natural alkaloid, attenuates cardiac ischemia-reperfusion injury in diabetic rats. The aim of present study was to investigate the effects of long-term berberine treatment on cardiac remodeling in diabetic rats and the underlying mechanisms. Diabetic rats induced by low-dose streptozotocin injection combined with 8 wk of high-fat diet displayed significant cardiac matrix collagen deposition and dysfunction, whereas berberine administration (200 mg·kg−1·day−1, gavage 4 wk) significantly ameliorated cardiac fibrosis and dysfunction and reduced cardiac IGF-1 receptor (IGF-1R) expression in diabetic rats. Interestingly, IGF-1R expression was upregulated in cardiac fibroblasts isolated from diabetic hearts or cultured in high-glucose conditions (30 mM). High glucose treatment or IGF-1R overexpression increased matrix metalloproteinase (MMP)-2/MMP-9 expression, α-smooth muscle actin (α-SMA), and collagen type I expression in cardiac fibroblasts. In contrast, berberine treatment significantly inhibited IGF-1R expression and exerted an antifibrotic effect in high glucose-cultured cardiac fibroblasts, as manifested by decreased MMP-2/MMP-9, α-SMA, and collagen type I expression, whereas IGF-1R siRNA plus berberine treatment did not further enhance this antifibrotic effect compared with berberine treatment alone. Taken together, long-term berberine treatment ameliorates cardiac fibrosis and dysfunction by downregulating IGF-1R expression in cardiac fibroblasts and subsequently reducing MMP-2/MMP-9, α-SMA, and collagen type I expression in diabetic hearts. The findings suggest the therapeutic potential of berberine for diabetic cardiomyopathy associated with cardiac fibrosis. NEW & NOTEWORTHY Berberine downregulated IGF-1 receptor expression and matrix metalloproteinase-2/matrix metalloproteinase-9 levels in cardiac fibroblasts and thus inhibited fibroblast differentiation and collagen overproduction in diabetic hearts, suggesting a novel mechanism for antifibrotic cardioprotection of berberine in type 2 diabetes.


2008 ◽  
Vol 29 (7) ◽  
pp. 898-906 ◽  
Author(s):  
I. Garcia-Bolao ◽  
B. Lopez ◽  
A. Macias ◽  
J. J. Gavira ◽  
P. Azcarate ◽  
...  

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 503-503
Author(s):  
Teresa Mortera-Blanco ◽  
Athanasios Mantalaris ◽  
Alexander Bismarck ◽  
Nicki Panoskaltsis

Abstract Abstract 503 The ability to expand cord blood (CB) cells ex vivo overcomes an important limitation to its wider clinical application in cellular therapies. The current practice of hematopoietic cell culture is based on two-dimensional (2D) tissue culture flasks or well plates which require either co-culture with allogeneic or xenogeneic stromal cells and the exogenous provision of several cytokines. This 2D culture environment is artificial and lacks the 3D cellular niches that characterise the in vivo hematopoietic inductive microenvironment. Specifically, the cultured cells are exposed to abnormally high cytokine concentrations, which may result in differentiation and loss of pluripotency. We have previously developed a 3D bone marrow biomimicry through the use of synthetic scaffolds made of poly (D,L-lactide-co-glycolide) (PLGA) and polyurethane (PU) coated with collagen type I. Our previous work has shown that these scaffolds, which were seeded with cord blood (CB) mononuclear cells (MNCs) at a cell density of 3-6×106cells per scaffold (5×5×5mm3), could successfully support long-term culture in the absence of exogenous growth factors for over 4 weeks. Specifically, the 3D biomimicry facilitated a 53-fold total MNC expansion, with an increase in the BFU-E and CFU-GM progenitor cell population. However, these cultures, although cytokine-free, contained 20-30% (v/v) fetal calf serum which can have both conducive and inhibitory effects on hematopoietic cell cultures due to the unknown composition and concentration of humoral factors contained within. Inclusion of serum in expansion-type cultures can limit the clinical application of the derived product. The serum-free and cytokine-free culture and expansion of hematopoietic cells has not been achieved until now. Herein, we report that for at least 4 weeks the polyurethane (PU) scaffolds coated with collagen type I were able to maintain and expand human CB MNCs. Furthermore the progenitor population, as determined by the colony forming unit assay, was also maintained and preferentially directed towards the granulocytic lineage, even though the CFU-GEMMs declined. Immunophenotypic analysis of the extracted cells confirmed the presence of erythroid precursors (CD71+CD45-) as well as early maturing myeloid cells. In contrast, the 2D cytokine- and serum-free cultures collapsed within 3-4 days. We hypothesized that the 3D biomimicry was able to facilitate serum- and cytokine-free conditions because it can recapitulate the three-dimensional architecture of the human bone marrow. This hypothesis was supported by scanning electron microscopy of the central sections of the scaffolds that showed the migration of cells within the pores and establishment of “niche-like” structures. In conclusion, this novel 3D culture system is capable of long-term, cytokine- and serum-free expansion of haematopoietic cells from cord blood, enabling the study of haematopoiesis as well as facilitating the expansion of cells for future clinical applications. Disclosures: No relevant conflicts of interest to declare.


2015 ◽  
Vol 2015 ◽  
pp. 1-5 ◽  
Author(s):  
Elżbieta Skowrońska-Jóźwiak ◽  
Krzysztof C. Lewandowski ◽  
Zbigniew Adamczewski ◽  
Kinga Krawczyk-Rusiecka ◽  
Andrzej Lewiński

Sclerostin, a protein expressed by osteocytes, is a negative regulator of bone formation. The aim of the study was to investigate the relationship between parathyroid hormone (PTH) and markers of bone metabolism and changes of sclerostin concentrations before and after treatment of hyperthyroidism.Patients and Methods. The study involved 33 patients (26 women), age (mean ± SD) 48 ± 15 years, with hyperthyroidism. Serum sclerostin, PTH, calcium, and bone markers [osteocalcin (OC) and collagen type I cross-linked C-telopeptide I (CTX)] were measured at diagnosis of hyperthyroidism and after treatment with thiamazole.Results. After treatment of hyperthyroidism a significant decrease in free T3(FT3) and free T4(FT4) concentrations was accompanied by marked decrease of serum sclerostin (from 43.7 ± 29.3 to 28.1 ± 18.4 pmol/L;p<0.001), OC (from 35.6 ± 22.0 to 27.0 ± 14.3 ng/mL;p<0.001), and CTX (from 0.49 ± 0.35 to 0.35 ± 0.23 ng/dL;p<0.005), accompanied by an increase of PTH (from 29.3 ± 14.9 to 39.8 ± 19.8;p<0.001). During hyperthyroidism there was a positive correlation between sclerostin and CTX (rs=0.41,p<0.05) and between OC and thyroid hormones (with FT3  rs=0.42, with FT4  rs=0.45,p<0.05).Conclusions. Successful treatment of hyperthyroidism results in a significant decrease in serum sclerostin and bone markers concentrations, accompanied by an increase of PTH.


2014 ◽  
Vol 191 (4S) ◽  
Author(s):  
Lisa Daum ◽  
Martin Vaegler ◽  
Sabine Maurer ◽  
Jens Mundhenk ◽  
Bastian Amend ◽  
...  

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