scholarly journals Increased macrophage-derived SPARC precedes collagen deposition in myocardial fibrosis

2018 ◽  
Vol 315 (1) ◽  
pp. H92-H100 ◽  
Author(s):  
Lindsay T. McDonald ◽  
Michael R. Zile ◽  
Yuhua Zhang ◽  
An O. Van Laer ◽  
Catalin F. Baicu ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Time Course ◽  
Pressure Overload ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Fibrillar Collagen ◽  
Collagen Deposition ◽  
Myocardial Stiffness ◽  
Insoluble Collagen

Myocardial fibrosis and the resultant increases in left ventricular stiffness represent pivotal consequences of chronic pressure overload (PO) that impact both functional capacity and the rates of morbid and mortal events. However, the time course and cellular mechanisms that underlie PO-induced fibrosis have not been completely defined. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that has been shown to be required for insoluble collagen deposition and increased myocardial stiffness in response to PO in mice. As macrophages are associated with increases in fibrillar collagen, the hypothesis that macrophages represent a source of increased SPARC production in the PO myocardium was tested. The time course of changes in the myocardial macrophage population was compared with changes in procollagen type I mRNA, production of SPARC, fibrillar collagen accumulation, and diastolic stiffness. In PO hearts, mRNA encoding collagen type I was increased at 3 days, whereas increases in levels of total collagen protein did not occur until 1 wk and were followed by increases in insoluble collagen at 2 wk. Increases in muscle stiffness were not detected before increases in insoluble collagen content (>1 wk). Significant increases in myocardial macrophages that coincided with increased SPARC were found but did not coincide with increases in mRNA encoding collagen type I. Furthermore, immunohistochemistry and flow cytometry identified macrophages as a cellular source of SPARC. We conclude that myocardial macrophages play an important role in the time-dependent increases in SPARC that enhance postsynthetic collagen processing, insoluble collagen content, and myocardial stiffness and contribute to the development of fibrosis. NEW & NOTEWORTHY Myocardial fibrosis and the resultant increases in left ventricular and myocardial stiffness represent pivotal consequences of chronic pressure overload. In this study a murine model of cardiac fibrosis induced by pressure overload was used to establish a time course of collagen expression, collagen deposition, and cardiac macrophage expansion.

scholarly journals Effects of the absence of procollagen C-endopeptidase enhancer-2 on myocardial collagen accumulation in chronic pressure overload

2012 ◽  
Vol 303 (2) ◽  
pp. H234-H240 ◽  
Author(s):  
Catalin F. Baicu ◽  
Yuhua Zhang ◽  
An O. Van Laer ◽  
Ludivine Renaud ◽  
Michael R. Zile ◽  
...  
Keyword(s):  
Cardiac Fibroblasts ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Bone Morphogenic Protein ◽  
Collagen Content ◽  
Fibrillar Collagen ◽  
Collagen Deposition ◽  
Myocardial Stiffness ◽  
Collagen Accumulation

Cardiac interstitial fibrillar collagen accumulation, such as that associated with chronic pressure overload (PO), has been shown to impair left ventricular diastolic function. Therefore, insight into cellular mechanisms that mediate excessive collagen deposition in the myocardium is pivotal to this important area of research. Collagen is secreted as a soluble procollagen molecule with NH2- and COOH (C)-terminal propeptides. Cleavage of these propeptides is required for collagen incorporation to insoluble collagen fibrils. The C-procollagen proteinase, bone morphogenic protein 1, cleaves the C-propeptide of procollagen. Procollagen C-endopeptidase enhancer (PCOLCE) 2, an enhancer of bone morphogenic protein-1 activity in vitro, is expressed at high levels in the myocardium. However, whether the absence of PCOLCE2 affects collagen content at baseline or after PO induced by transverse aortic constriction (TAC) has never been examined. Accordingly, in vivo procollagen processing and deposition were examined in wild-type (WT) and PCOLCE2-null mice. No significant differences in collagen content or myocardial stiffness were detected in non-TAC (control) PCOLCE2-null versus WT mice. After TAC-induced PO, PCOLCE2-null hearts demonstrated a lesser collagen content (PCOLCE2-null TAC collagen volume fraction, 0.41% ± 0.07 vs. WT TAC, 1.2% ± 0.3) and lower muscle stiffness compared with WT PO hearts [PCOLCE2-null myocardial stiffness (β), 0.041 ± 0.002 vs. WT myocardial stiffness, 0.065 ± 0.001]. In addition, in vitro, PCOLCE2-null cardiac fibroblasts exhibited reductions in efficiency of C-propeptide cleavage, as demonstrated by increases in procollagen α1(I) and decreased levels of processed collagen α1(I) versus WT cardiac fibroblasts. Hence, PCOLCE2 is required for efficient procollagen processing and deposition of fibrillar collagen in the PO myocardium. These results support a critical role for procollagen processing in the regulation of collagen deposition in the heart.

scholarly journals Time course of right ventricular pressure-overload induced myocardial fibrosis: relationship to changes in fibroblast postsynthetic procollagen processing

2012 ◽  
Vol 303 (9) ◽  
pp. H1128-H1134 ◽  
Author(s):  
Catalin F. Baicu ◽  
Jiayu Li ◽  
Yuhua Zhang ◽  
Harinath Kasiganesan ◽  
George Cooper ◽  
...  
Keyword(s):  
Myocardial Fibrosis ◽  
Time Course ◽  
Volume Fraction ◽  
Diastolic Pressure ◽  
Pressure Overload ◽  
Collagen Content ◽  
Fibrillar Collagen ◽  
Hypertrophic Growth ◽  
Insoluble Collagen ◽  
Sparc Expression

Myocardial fibrillar collagen is considered an important determinant of increased ventricular stiffness in pressure-overload (PO)-induced cardiac hypertrophy. Chronic PO was created in feline right ventricles (RV) by pulmonary artery banding (PAB) to define the time course of changes in fibrillar collagen content after PO using a nonrodent model and to determine whether this time course was dependent on changes in fibroblast function. Total, soluble, and insoluble collagen (hydroxyproline), collagen volume fraction (CVF), and RV end-diastolic pressure were assessed 2 days and 1, 2, 4, and 10 wk following PAB. Fibroblast function was assessed by quantitating the product of postsynthetic processing, insoluble collagen, and levels of SPARC (secreted protein acidic and rich in cysteine), a protein that affects procollagen processing. RV hypertrophic growth was complete 2 wk after PAB. Changes in RV collagen content did not follow the same time course. Two weeks after PAB, there were elevations in total collagen (control RV: 8.84 ± 1.03 mg/g vs. 2-wk PAB: 11.50 ± 0.78 mg/g); however, increased insoluble fibrillar collagen, as measured by CVF, was not detected until 4 wk after PAB (control RV CVF: 1.39 ± 0.25% vs. 4-wk PAB: 4.18 ± 0.87%). RV end-diastolic pressure was unchanged at 2 wk, but increased until 4 wk after PAB. RV fibroblasts isolated after 2-wk PAB had no changes in either insoluble collagen or SPARC expression; however, increases in insoluble collagen and in levels of SPARC were detected in RV fibroblasts from 4-wk PAB. Therefore, the time course of PO-induced RV hypertrophy differs significantly from myocardial fibrosis and diastolic dysfunction. These temporal differences appear dependent on changes in fibroblast function.

Role of aldosterone in angiotensin II-induced cardiac and aortic inflammation, fibrosis, and hypertrophy

2005 ◽  
Vol 83 (11) ◽  
pp. 999-1006 ◽  
Author(s):  
Mario Fritsch Neves ◽  
Farhad Amiri ◽  
Agostino Virdis ◽  
Quy N Diep ◽  
Ernesto L Schiffrin
Keyword(s):  
Inflammatory Markers ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Collagen Deposition ◽  
Ang Ii ◽  
Mobility Shift ◽  
Transcription Factor Activation ◽  
Mobility Shift Assay ◽  
Cell Adhesion Molecule 1

Activation of the renin–angiotensin–aldosterone system is associated with increased extracellular matrix and inflammatory markers in the cardiovascular system. We evaluated the effects of aldosterone antagonism on cardiovascular structure, collagen deposition, and expression of inflammatory markers in 2-week angiotensin (Ang) II-infused rats (120 ng·kg–1·min–1, s.c.) ± spironolactone or hydralazine (25 mg·kg–1·d–1). Aortic and cardiac collagen density was evaluated with Sirius red staining. NFκB and AP-1 were measured by a electrophoretic mobility shift assay, and ED-1 (macrophage marker) and vascular cell adhesion molecule-1 (VCAM-1) were measured by immunohistochemistry. Ang II increased blood pressure (176 ± 2 mmHg vs. 115 ± 1 mmHg in controls, p < 0.01), which was attenuated by spironolactone (147 ± 4 mmHg, p < 0.01) and prevented by hydralazine (124 ± 2 mmHg, p < 0.01). Ang II enhanced left ventricular interstitial collagen type I/III deposition (4.1% ± 0.1% vs. 3.1% ± 0.2%, p < 0.05), and this was attenuated by spironolactone but not hydralazine. Ang II-induced cardiac perivascular fibrosis was prevented by spironolactone and hydralazine. Ang II significantly increased cardiac AP-1 activity and ED-1 expression, which was prevented by spironolactone only. Ang II-enhanced NFκB activity, and VCAM-1 expression was reduced by spironolactone and hydralazine, whereas aortic hypertrophy was prevented by spironolactone and slightly reduced by hydralazine. In conclusion, blockade of mineralocorticoid receptors with spironolactone inhibited Ang II-induced aortic hypertrophy, cardiac transcription factor activation, upregulation of downstream inflammatory markers, and collagen deposition, thus preventing Ang II-induced cardiovascular damage.Key words: collagen, heart, aorta, spironolactone, inflammation.

scholarly journals HMGB1 Aggravates Pressure Overload-Induced Left Ventricular Dysfunction by Promoting Myocardial Fibrosis

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Lei Zhang ◽  
Ying Yu ◽  
Peng Yu ◽  
Jian Wu ◽  
Aijun Sun ◽  
...  
Keyword(s):  
Cardiac Fibrosis ◽  
Collagen Type ◽  
Cardiac Injury ◽  
Pressure Overload ◽  
High Mobility ◽  
Collagen Type I ◽  
Left Ventricular ◽  
Type I ◽  
Lv Dysfunction

Aim. Fibrosis had important effects on pressure overload-induced left ventricular (LV) dysfunction. High-mobility group box 1 (HMGB1), which was closely associated with fibrosis, was involved in the pressure overload-induced cardiac injury. This study determines the role of HMGB1 in LV dysfunction under pressure overload. Methods. Transverse aortic constriction (TAC) operation was performed on male C57BL/6J mice to build the model of pressure overload, while HMGB1 or PBS was injected into the LV wall. Cardiac function, collagen volume, and relevant genes were detected. Results. Echocardiography demonstrated that the levels of LV ejection fraction (LVEF) were markedly decreased on day 28 after TAC, which was consistent with raised collagen in the myocardium. Moreover, we found that the exposure of mice to TAC + HMGB1 is associated with higher mortality, BNP, and collagen volume in the myocardium and lower LVEF. In addition, real-time PCR showed that the expression of collagen type I, TGF-β, and MMP2 markedly increased in the myocardium after TAC, while HMGB1 overexpression further raised the TGF-β expression but not collagen type I and MMP2 expressions. Conclusion. This study indicated that exogenous HMGB1 overexpression in the myocardium aggravated the pressure overload-induced LV dysfunction by promoting cardiac fibrosis, which may be mediated by increasing the TGF-β expression.

scholarly journals Oncofetal Protein CRIPTO Is Involved in Wound Healing and Fibrogenesis in the Regenerating Liver and Is Associated with the Initial Stages of Cardiac Fibrosis

Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3325
Author(s):  
Sofia Karkampouna ◽  
Danny van der Helm ◽  
Mario Scarpa ◽  
Bart van Hoek ◽  
Hein W. Verspaget ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Mouse Models ◽  
Cardiac Fibrosis ◽  
Ex Vivo ◽  
Pressure Overload ◽  
Collagen Type I ◽  
Type I ◽  
Liver Fibrogenesis ◽  
End Stage

Oncofetal protein, CRIPTO, is silenced during homeostatic postnatal life and often re-expressed in different neoplastic processes, such as hepatocellular carcinoma. Given the reactivation of CRIPTO in pathological conditions reported in various adult tissues, the aim of this study was to explore whether CRIPTO is expressed during liver fibrogenesis and whether this is related to the disease severity and pathogenesis of fibrogenesis. Furthermore, we aimed to identify the impact of CRIPTO expression on fibrogenesis in organs with high versus low regenerative capacity, represented by murine liver fibrogenesis and adult murine heart fibrogenesis. Circulating CRIPTO levels were measured in plasma samples of patients with cirrhosis registered at the waitlist for liver transplantation (LT) and 1 year after LT. The expression of CRIPTO and fibrotic markers (αSMA, collagen type I) was determined in human liver tissues of patients with cirrhosis (on a basis of viral hepatitis or alcoholic disease), in cardiac tissue samples of patients with end-stage heart failure, and in mice with experimental liver and heart fibrosis using immuno-histochemical stainings and qPCR. Mouse models with experimental chronic liver fibrosis, induced with multiple shots of carbon tetrachloride (CCl4) and acute liver fibrosis (one shot of CCl4), were evaluated for CRIPTO expression and fibrotic markers. CRIPTO was overexpressed in vivo (Adenoviral delivery) or functionally sequestered by ALK4Fc ligand trap in the acute liver fibrosis mouse model. Murine heart tissues were evaluated for CRIPTO and fibrotic markers in three models of heart injury following myocardial infarction, pressure overload, and ex vivo induced fibrosis. Patients with end-stage liver cirrhosis showed elevated CRIPTO levels in plasma, which decreased 1 year after LT. Cripto expression was observed in fibrotic tissues of patients with end-stage liver cirrhosis and in patients with heart failure. The expression of CRIPTO in the liver was found specifically in the hepatocytes and was positively correlated with the Model for End-stage Liver Disease (MELD) score for end-stage liver disease. CRIPTO expression in the samples of cardiac fibrosis was limited and mostly observed in the interstitial cells. In the chronic and acute mouse models of liver fibrosis, CRIPTO-positive cells were observed in damaged liver areas around the central vein, which preceded the expression of αSMA-positive stellate cells, i.e., mediators of fibrosis. In the chronic mouse models, the fibrosis and CRIPTO expression were still present after 11 weeks, whereas in the acute model the liver regenerated and the fibrosis and CRIPTO expression resolved. In vivo overexpression of CRIPTO in this model led to an increase in fibrotic markers, while blockage of CRIPTO secreted function inhibited the extent of fibrotic areas and marker expression (αSMA, Collagen type I and III) and induced higher proliferation of residual healthy hepatocytes. CRIPTO expression was also upregulated in several mouse models of cardiac fibrosis. During myocardial infarction CRIPTO is upregulated initially in cardiac interstitial cells, followed by expression in αSMA-positive myofibroblasts throughout the infarct area. After the scar formation, CRIPTO expression decreased concomitantly with the αSMA expression. Temporal expression of CRIPTO in αSMA-positive myofibroblasts was also observed surrounding the coronary arteries in the pressure overload model of cardiac fibrosis. Furthermore, CRIPTO expression was upregulated in interstitial myofibroblasts in hearts cultured in an ex vivo model for cardiac fibrosis. Our results are indicative for a functional role of CRIPTO in the induction of fibrogenesis as well as a potential target in the antifibrotic treatments and stimulation of tissue regeneration.

Chronic urotensin-II infusion induces diastolic dysfunction and enhances collagen production in rats

2010 ◽  
Vol 298 (2) ◽  
pp. H608-H613 ◽  
Author(s):  
Lavinia Tran ◽  
Andrew R. Kompa ◽  
Will Kemp ◽  
Arintaya Phrommintikul ◽  
Bing H. Wang ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Intracellular Signaling ◽  
Cardiac Myocyte ◽  
Collagen Type I ◽  
Left Ventricular ◽  
High Dose ◽  
Type I ◽  
Urotensin Ii ◽  
Rock Inhibitor

The vasoactive peptide urotensin-II (U-II) is likely to play a key causal role in cardiac remodeling that ultimately leads to heart failure. Its contribution, specifically to the development of diastolic dysfunction and the downstream intracellular signaling, however, remains unresolved. This study interrogates the effect of chronic U-II infusion in normal rats on cardiac structure and function. The contribution of Rho kinase (ROCK) signaling to these pathophysiological changes is evaluated in cell culture studies. Chronic high-dose U-II infusion over 4 wk significantly impaired diastolic function in rats on echocardiography-derived Doppler indexes, including E-wave deceleration time (vehicle 56.7 ± 3.3 ms, U-II 118.0 ± 21.5 ms; P < 0.01) and mitral valve annulus peak early/late diastolic tissue velocity (vehicle 2.01 ± 0.19 ms, U-II 1.04 ± 0.25 ms; P < 0.01). A lower dose of U-II infusion (1 nmol·kg−1·h−1) yielded comparable changes. Diastolic dysfunction was accompanied by molecular [significant increases in procollagen-α1(I) gene expression on real-time PCR] and morphological (increases in total collagen, P < 0.05, and collagen type-I protein deposition, P < 0.001) evidence of left ventricular (LV) fibrosis following high-dose U-II infusion. The ROCK inhibitor GSK-576371 (10−7 to 10−5 M) elicited concentration-dependent inhibition of U-II (10−7 M)-stimulated cardiac fibroblast collagen synthesis and cardiac myocyte protein synthesis. Chronic U-II infusion causes diastolic dysfunction, caused by fibrosis of the LV. The in vitro data suggest that this may be in part occurring via a ROCK-dependent pathway.

scholarly journals Collagen microarchitecture mechanically controls myofibroblast differentiation

2020 ◽  
Vol 117 (21) ◽  
pp. 11387-11398 ◽  
Author(s):  
Bo Ri Seo ◽  
Xingyu Chen ◽  
Lu Ling ◽  
Young Hye Song ◽  
Adrian A. Shimpi ◽  
...  
Keyword(s):  
Collagen Type ◽  
Collagen Type I ◽  
Type I ◽  
Myofibroblast Differentiation ◽  
Dependent Manner ◽  
Fibrillar Collagen ◽  
Collagen Gels ◽  
Gelation Temperature ◽  
Rheological Characterization ◽  
Fiber Thickness

Altered microarchitecture of collagen type I is a hallmark of wound healing and cancer that is commonly attributed to myofibroblasts. However, it remains unknown which effect collagen microarchitecture has on myofibroblast differentiation. Here, we combined experimental and computational approaches to investigate the hypothesis that the microarchitecture of fibrillar collagen networks mechanically regulates myofibroblast differentiation of adipose stromal cells (ASCs) independent of bulk stiffness. Collagen gels with controlled fiber thickness and pore size were microfabricated by adjusting the gelation temperature while keeping their concentration constant. Rheological characterization and simulation data indicated that networks with thicker fibers and larger pores exhibited increased strain-stiffening relative to networks with thinner fibers and smaller pores. Accordingly, ASCs cultured in scaffolds with thicker fibers were more contractile, expressed myofibroblast markers, and deposited more extended fibronectin fibers. Consistent with elevated myofibroblast differentiation, ASCs in scaffolds with thicker fibers exhibited a more proangiogenic phenotype that promoted endothelial sprouting in a contractility-dependent manner. Our findings suggest that changes of collagen microarchitecture regulate myofibroblast differentiation and fibrosis independent of collagen quantity and bulk stiffness by locally modulating cellular mechanosignaling. These findings have implications for regenerative medicine and anticancer treatments.

scholarly journals Time course of left ventricular remodelling and mechanics after aortic valve surgery: aortic stenosis vs. aortic regurgitation

2019 ◽  
Vol 20 (10) ◽  
pp. 1105-1111
Author(s):  
E Mara Vollema ◽  
Gurpreet K Singh ◽  
Edgard A Prihadi ◽  
Madelien V Regeer ◽  
See Hooi Ewe ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Aortic Stenosis ◽  
Aortic Regurgitation ◽  
Time Course ◽  
Pressure Overload ◽  
Volume Overload ◽  
Left Ventricular ◽  
Valve Surgery ◽  
Aortic Valve Surgery ◽  
Lv Mass

Abstract Aims Pressure overload in aortic stenosis (AS) and both pressure and volume overload in aortic regurgitation (AR) induce concentric and eccentric hypertrophy, respectively. These structural changes influence left ventricular (LV) mechanics, but little is known about the time course of LV remodelling and mechanics after aortic valve surgery (AVR) and its differences in AS vs. AR. The present study aimed to characterize the time course of LV mass index (LVMI) and LV mechanics [by LV global longitudinal strain (LV GLS)] after AVR in AS vs. AR. Methods and results Two hundred and eleven (61 ± 14 years, 61% male) patients with severe AS (63%) or AR (37%) undergoing surgical AVR with routine echocardiographic follow-up at 1, 2, and/or 5 years were evaluated. Before AVR, LVMI was larger in AR patients compared with AS. Both groups showed moderately impaired LV GLS, but preserved LV ejection fraction. After surgery, both groups showed LV mass regression, although a more pronounced decline was seen in AR patients. Improvement in LV GLS was observed in both groups, but characterized by an initial decline in AR patients while LV GLS in AS patients remained initially stable. Conclusion In severe AS and AR patients undergoing AVR, LV mass regression and changes in LV GLS are similar despite different LV remodelling before AVR. In AR, relief of volume overload led to reduction in LVMI and an initial decline in LV GLS. In contrast, relief of pressure overload in AS was characterized by a stable LV GLS and more sustained LV mass regression.

Limb bud mesenchyme cultured under tensile strain remodel collagen type I tubes to produce fibrillar collagen type II

Biorheology ◽  
2009 ◽  
Vol 46 (6) ◽  
pp. 439-450 ◽  
Author(s):  
Jennifer R. Amos ◽  
Shigeng Li ◽  
Michael Yost ◽  
Harry Phloen ◽  
Jay D. Potts
Keyword(s):  
Tensile Strain ◽  
Collagen Type ◽  
Collagen Type I ◽  
Limb Bud ◽  
Type I ◽  
Fibrillar Collagen ◽  
Type Ii ◽  
Collagen Type Ii
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