Unloading-induced remodeling in the normal and hypertrophic left ventricle

2003 ◽  
Vol 284 (6) ◽  
pp. H2061-H2068 ◽  
Author(s):  
Brian S. McGowan ◽  
Christopher B. Scott ◽  
Anbin Mu ◽  
Richard J. McCormick ◽  
D. Paul Thomas ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Small Animal ◽  
Left Ventricular ◽  
Reverse Remodeling ◽  
Cross Linking ◽  
Heterotopic Transplantation ◽  
Collagen Concentration ◽  
Matrix Interactions ◽  
Normal Controls ◽  
Collagen Cross Linking

To date, no study has assessed the degree of similarity between left ventricular (LV) reverse remodeling and atrophic remodeling. Stable LV hypertrophy was induced by creation of an arteriovenous fistula (AVF) in Lewis rats (32 days). LV unloading was induced by heterotopic transplantation of normal (NL-HT) and/or hypertrophic (AVF-HT) hearts (7 days). We compared indexes of remodeling in AVF, NL-HT, and AVF-HT groups with those of normal controls. LV unloading induced decreases in cardiomyocyte size in NL-HT and AVF-HT hearts. NL-HT and AVF-HT LV were both characterized by relative increases in collagen concentration that were largely a reflection of decreases in myocyte volume. NL-HT and AVF-HT LV were associated with similar increases in matrix metalloproteinase (MMP-2 and -9) zymographic activity, without change in the abundance of the tissue inhibitors of the MMPs. In contrast, AVF-HT, but not NL-HT, was associated with a dramatic increase in collagen cross-linking. Our findings suggest an overall similarity in the response of the normal and hypertrophic LV to surgical unloading. However, the dramatic increase in collagen cross-linking after just 1 wk of unloading suggests a potential difference in the dynamics of collagen metabolism between the two models. Further studies will be required to determine the precise molecular mechanisms responsible for these differences in extracellular matrix regulation. However, with respect to these and related issues, heterotopic transplantation of hypertrophied hearts will be a useful small animal model for defining mechanisms of myocyte-matrix interactions during decreased loading conditions.

scholarly journals Glycated collagen cross-linking alters cardiac mechanics in volume-overload hypertrophy

2003 ◽  
Vol 284 (4) ◽  
pp. H1277-H1284 ◽  
Author(s):  
Keith L. Herrmann ◽  
Andrew D. McCulloch ◽  
Jeffrey H. Omens
Keyword(s):  
Volume Overload ◽  
Cardiac Mechanics ◽  
Left Ventricular ◽  
Cross Linking ◽  
Collagen Concentration ◽  
Longitudinal Stiffness ◽  
Diastolic Compliance ◽  
Cross Links ◽  
Modify Collagen ◽  
Collagen Cross Linking

Alteration of hemodynamic loading induces remodeling that includes changes in myocardial properties and extracellular matrix structure. We investigated the hypothesis that cardiac hypertrophy due to volume overload produces changes in myocardial diastolic mechanics and stiffness that are in part due to alterations in advanced glycation end-product (AGE) collagen cross-linking. Rats developed volume overload induced by arteriovenous fistula (AVF). To assess the dependence of AGE cross-linking on mechanics, we prevented AGE formation by administering the drug aminoguanidine (AG) to one group of AVF rats (AG+AVF). Volume overload did not modify collagen concentration. Right ventricular AGE cross-links were modestly elevated in AVF hearts but were significantly reduced by AG. AVF rats exhibited significantly increased septal AGE cross-links that were inhibited in the AG+AVF group. AVF-induced increases in left ventricular longitudinal stiffness and septal circumferential stiffness were prevented in AG+AVF hearts. Volume overload appears to regionally modify AGE collagen cross-linking and stiffness, and AG treatment prevented these increases, demonstrating that AGE cross-linking plays a role in mediating diastolic compliance in volume-overload hypertrophy.

scholarly journals Moderate Loss of the Extracellular Matrix Proteoglycan Lumican Attenuates Cardiac Fibrosis in Mice Subjected to Pressure Overload

Cardiology ◽  
2020 ◽  
Vol 145 (3) ◽  
pp. 187-198 ◽  
Author(s):  
Naiyereh Mohammadzadeh ◽  
Arne Olav Melleby ◽  
Sheryl Palmero ◽  
Ivar Sjaastad ◽  
Shukti Chakravarti ◽  
...  
Keyword(s):  
Heart Failure ◽  
Extracellular Matrix ◽  
Diastolic Dysfunction ◽  
Cardiac Fibrosis ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Cross Linking ◽  
Myocardial Remodeling ◽  
Functional Changes ◽  
Collagen Cross Linking

Introduction: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic so­lutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). Methods and Results: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/–) hearts compared to wild-type (WT) controls. LUM+/– mice were subjected to AB. There was no difference in survival between LUM+/– and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/– and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/– mice. LUM+/– hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/– compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/– and WT mice post-AB, as assessed by histology and qPCR. Conclusions: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.

scholarly journals N-acetyl-seryl-aspartyl-lysyl-proline reduces cardiac collagen cross-linking and inflammation in angiotensin II-induced hypertensive rats

2013 ◽  
Vol 126 (1) ◽  
pp. 85-94 ◽  
Author(s):  
Germán E. González ◽  
Nour-Eddine Rhaleb ◽  
Pablo Nakagawa ◽  
Tang-Dong Liao ◽  
Yunhe Liu ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Lysyl Oxidase ◽  
Left Ventricular ◽  
Cross Linking ◽  
Lymphocyte Infiltration ◽  
Total Collagen ◽  
Induced Hypertension ◽  
Collagen Cross Linking

We have reported previously that Ac-SDKP (N-acetyl-seryl-aspartyl-lysyl-proline) reduces fibrosis and inflammation (in macrophages and mast cells). However, it is not known whether Ac-SDKP decreases collagen cross-linking and lymphocyte infiltration; lymphocytes modulate both collagen cross-linking and ECM (extracellular matrix) formation in hypertension. Thus we hypothesized that (i) in AngII (angiotensin II)-induced hypertension, Ac-SDKP prevents increases in cross-linked and total collagen by down-regulating LOX (lysyl oxidase), the enzyme responsible for cross-linking, and (ii) these effects are associated with decreased pro-fibrotic cytokine TGFβ (transforming growth factor β) and the pro-inflammatory transcription factor NF-κB (nuclear factor κB) and CD4+/CD8+ lymphocyte infiltration. We induced hypertension in rats by infusing AngII either alone or combined with Ac-SDKP for 3 weeks. Whereas Ac-SDKP failed to lower BP (blood pressure) or LV (left ventricular) hypertrophy, it did prevent AngII-induced increases in (i) cross-linked and total collagen, (ii) LOX mRNA expression and LOXL1 (LOX-like 1) protein, (iii) TGFβ expression, (iv) nuclear translocation of NF-κB, (v) CD4+/CD8+ lymphocyte infiltration, and (vi) CD68+ macrophages infiltration. In addition, we found a positive correlation between CD4+ infiltration and LOXL1 expression. In conclusion, the effect of Ac-SDKP on collagen cross-linking and total collagen may be due to reduced TGFβ1, LOXL1, and lymphocyte and macrophage infiltration, and its effect on inflammation could be due to lower NF-κB.

scholarly journals Differential Regulation of MicroRNAs in End-Stage Failing Hearts Is Associated with Left Ventricular Assist Device Unloading

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Cristina Barsanti ◽  
Maria Giovanna Trivella ◽  
Romina D’Aurizio ◽  
Mariama El Baroudi ◽  
Mario Baumgart ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Ventricular Assist Devices ◽  
Reverse Remodeling ◽  
Left Ventricular Assist Devices ◽  
Ventricular Assist ◽  
Off Pump ◽  
Mechanical Unloading ◽  
Left Ventricular Assist ◽  
End Stage

Mechanical unloading by left ventricular assist devices (LVADs) in advanced heart failure (HF), in addition to improving symptoms and end-organ perfusion, is supposed to stimulate cellular and molecular responses which can reverse maladaptive cardiac remodeling. As microRNAs (miRNAs) are key regulators in remodeling processes, a comparative miRNA profiling in transplanted hearts of HF patients with/without LVAD assistance could aid to comprehend underlying molecular mechanisms. Next generation sequencing (NGS) was used to analyze miRNA differential expression in left ventricles of HF patients who underwent heart transplantation directly (n=9) or following a period of LVAD support (n=8). After data validation by quantitative real-time PCR, association with functional clinical parameters was investigated. Bioinformatics’ tools were then used for prediction of putative targets of modulated miRNAs and relative pathway enrichment. The analysis revealed 13 upregulated and 10 downregulated miRNAs in failing hearts subjected to LVAD assistance. In particular, the expression level of some of them (miR-338-3p, miR-142-5p and -3p, miR-216a-5p, miR-223-3p, miR-27a-5p, and miR-378g) showed correlation with off-pump cardiac index values. Predicted targets of these miRNAs were involved in focal adhesion/integrin pathway and in actin cytoskeleton regulation. The identified miRNAs might contribute to molecular regulation of reverse remodeling and heart recovery mechanisms.

Copper deficiency alters collagen types and covalent cross-linking in swine myocardium and cardiac valves

1993 ◽  
Vol 264 (6) ◽  
pp. H2154-H2161 ◽  
Author(s):  
R. K. Vadlamudi ◽  
R. J. McCormick ◽  
D. M. Medeiros ◽  
J. Vossoughi ◽  
M. L. Failla
Keyword(s):  
Cardiac Hypertrophy ◽  
Copper Deficiency ◽  
Left Ventricular ◽  
Cross Linking ◽  
Type Iii Collagen ◽  
Cardiac Valves ◽  
Dietary Copper ◽  
Organ Systems ◽  
The Impact ◽  
Collagen Cross Linking

Dietary copper deficiency induces alterations of connective tissue metabolism that are associated with lesions in cardiovascular and other organ systems. To determine the impact of copper deficiency on characteristics of collagen in porcine myocardium and cardiac valves, weaned pigs were fed diets with adequate or deficient levels of copper. Although dietary copper did not affect the concentration of collagen in either myocardium or bicuspid valves, the degree of collagen cross-linking, as assessed by the level of hydroxylysylpyridinoline, was lower in both tissues of copper-deficient pigs. Proportions of type III collagen were increased in the left ventricle and bicuspid valves of copper-deficient pigs. Copper deficiency induced extensive remodeling, however, of the collagen fraction of cardiac interstitium. Reduction in left ventricular collagen cross-linking may provide the stimulus for the development of cardiac hypertrophy, which characterizes severe copper deficiency, by increasing the compliance of the ventricular wall. The shift in the phenotypic profile of collagen that is associated with this cardiac hypertrophy indicates synthesis of new collagen, which could affect collagen cross-linking irrespective of copper status.

scholarly journals Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Petra Büttner ◽  
Lukas Feistner ◽  
Philipp Lurz ◽  
Holger Thiele ◽  
Joshua D. Hutcheson ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Aortic Valve ◽  
Aortic Valve Disease ◽  
Molecular Mechanisms ◽  
Left Ventricular ◽  
Valve Disease ◽  
Reverse Remodeling ◽  
Calcific Aortic Valve Disease ◽  
Ecm Remodeling ◽  
The Individual

Calcific aortic valve disease (CAVD) is a highly prevalent and progressive disorder that ultimately causes gradual narrowing of the left ventricular outflow orifice with ensuing devastating hemodynamic effects on the heart. Calcific mineral accumulation is the hallmark pathology defining this process; however, fibrotic extracellular matrix (ECM) remodeling that leads to extensive deposition of fibrous connective tissue and distortion of the valvular microarchitecture similarly has major biomechanical and functional consequences for heart valve function. Significant advances have been made to unravel the complex mechanisms that govern these active, cell-mediated processes, yet the interplay between fibrosis and calcification and the individual contribution to progressive extracellular matrix stiffening require further clarification. Specifically, we discuss (1) the valvular biomechanics and layered ECM composition, (2) patterns in the cellular contribution, temporal onset, and risk factors for valvular fibrosis, (3) imaging valvular fibrosis, (4) biomechanical implications of valvular fibrosis, and (5) molecular mechanisms promoting fibrotic tissue remodeling and the possibility of reverse remodeling. This review explores our current understanding of the cellular and molecular drivers of fibrogenesis and the pathophysiological role of fibrosis in CAVD.

Inhibition of collagen cross-linking: effects on fibrillar collagen and ventricular diastolic function

1995 ◽  
Vol 269 (3) ◽  
pp. H863-H868 ◽  
Author(s):  
S. Kato ◽  
F. G. Spinale ◽  
R. Tanaka ◽  
W. Johnson ◽  
G. Cooper ◽  
...  
Keyword(s):  
Ventricular Volume ◽  
Left Ventricular ◽  
Collagen Content ◽  
Distribution Area ◽  
Cross Linking ◽  
Fibrillar Collagen ◽  
Volume Data ◽  
Myocardial Stiffness ◽  
And Function ◽  
Collagen Cross Linking

The fibrillar collagen network is postulated to be a primary determinant of left ventricular diastolic stiffness. This hypothesis was tested by examining the structural and physiological effects of a reduction in fibrillar collagen content and cross-linking in the intact left ventricle. Collagen cross-linking was inhibited by treating five normal adult pigs with beta-aminopropionitrile (BAPN; 10 g/day po) for 6 wk; five normal untreated pigs served as controls. Left ventricular volume, mass, and function were determined by simultaneous echocardiography and catheterization. Chamber stiffness, defined by pressure vs. volume data, and myocardial stiffness, defined by stress vs. dimension data, were determined from variably loaded beats during dextran infusion. Collagen distribution (% area) and integrity (% confluence) were determined by light microscopy. Collagen content was measured by hydroxyproline assay, and collagen cross-linking was measured by salt extraction. BAPN decreased collagen distribution (% area decreased from 12 +/- 1% in control to 7 +/- 1% in BAPN, P < 0.05), collagen integrity (% confluence decreased from 8 +/- 1% in control to 4 +/- 1% in BAPN, P < 0.05), collagen content (from 36 +/- 2 mg/g dry wt in control to 27 +/- 2 mg/g dry wt in BAPN, P < 0.05), and collagen cross-linking (extractable collagen increased from 21 +/- 2% in control to 28 +/- 2% in BAPN, P < 0.05). BAPN decreased chamber stiffness (0.13 +/- 0.02 in control to 0.06 +/- 0.01 in BAPN, P < 0.05) and myocardial stiffness (10.4 +/- 0.5 in control to 6.6 +/- 0.5 in BAPN, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Regional differences in LV collagen accumulation and mature cross-linking after myocardial infarction in rats

1994 ◽  
Vol 266 (1) ◽  
pp. H354-H359 ◽  
Author(s):  
R. J. McCormick ◽  
T. I. Musch ◽  
B. C. Bergman ◽  
D. P. Thomas
Keyword(s):  
Myocardial Infarction ◽  
Regional Differences ◽  
Interventricular Septum ◽  
Principal Component ◽  
Left Ventricular ◽  
Viable Myocardium ◽  
Heart Weight ◽  
Cross Linking ◽  
Free Wall ◽  
Collagen Concentration

To determine the extent of and any regional differences in remodeling response of the extracellular matrix (ECM) to myocardial infarction (MI), moderate-to-large transmural infarcts were surgically produced in left ventricular (LV) free wall of rats. Animals were killed 13 wk after surgery. In comparison to age-matched controls, infarction was associated with an overall increase in heart weight, which included hypertrophy of both the right ventricle and LV. Although the remaining viable myocardium in LV free wall was significantly reduced, the interventricular septum was hypertrophied some 30% compared with control tissues (247 +/- 9 vs. 189 +/- 8 mg). Collagen concentration more than doubled in remaining viable free wall (8.92 +/- 0.59 vs. 3.95 +/- 0.25 mg/100 mg, P < 0.0001), and a smaller but still highly significant 27% increase occurred (P < 0.01) in the more remote septum. Degree of covalent cross-linking of collagen fibrils as assessed by hydroxylysylpyridinoline (HP) concentration also revealed regional differences in response of the ECM to infarction. Although HP concentration was increased 60% in viable free wall (P < 0.05) post-MI, it was unchanged in the septum. With respect to collagen characteristics of the transmural infarct per se, the scar exhibited still further increases in both collagen and HP concentrations compared with the already elevated values for these two parameters in viable free wall. The results indicate that any evaluation of the remodeling response of viable myocardium post-MI must include not only the myocyte but also the ECM, the principal component of which is collagen.

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