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

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)

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00227.2012 ◽

2012 ◽

Vol 303 (2) ◽

pp. H234-H240 ◽

Cited By ~ 27

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.

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Mechanical Unloading During Left Ventricular Assist Device Support Increases Left Ventricular Collagen Cross-Linking and Myocardial Stiffness

Circulation ◽

10.1161/circulationaha.104.515106 ◽

2005 ◽

Vol 112 (3) ◽

pp. 364-374 ◽

Cited By ~ 135

Author(s):

Stefan Klotz ◽

Robert F. Foronjy ◽

Marc L. Dickstein ◽

Anguo Gu ◽

Ingrid M. Garrelds ◽

...

Keyword(s):

Left Ventricular Assist Device ◽

Left Ventricular ◽

Cross Linking ◽

Assist Device ◽

Ventricular Assist ◽

Myocardial Stiffness ◽

Mechanical Unloading ◽

Left Ventricular Assist ◽

Collagen Cross Linking ◽

Left Ventricular Collagen

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T-lymphocytes mediate left ventricular fibrillar collagen cross-linking and diastolic dysfunction in mice

Matrix Biology ◽

10.1016/j.matbio.2010.06.003 ◽

2010 ◽

Vol 29 (6) ◽

pp. 511-518 ◽

Cited By ~ 33

Author(s):

Qianli Yu ◽

Randy Vazquez ◽

Sherma Zabadi ◽

Ronald R. Watson ◽

Douglas F. Larson

Keyword(s):

T Lymphocytes ◽

Diastolic Dysfunction ◽

Left Ventricular ◽

Cross Linking ◽

Fibrillar Collagen ◽

Collagen Cross Linking

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Impact of sex and chronic resistance training on human patellar tendon dry mass, collagen content, and collagen cross-linking

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90607.2008 ◽

2009 ◽

Vol 296 (1) ◽

pp. R119-R124 ◽

Cited By ~ 21

Author(s):

Jennifer K. LeMoine ◽

Jonah D. Lee ◽

Todd A. Trappe

Keyword(s):

Resistance Training ◽

Patellar Tendon ◽

Structural Integrity ◽

Dry Mass ◽

Structural Features ◽

Collagen Content ◽

Cross Linking ◽

Wet Weight ◽

And Function ◽

Collagen Cross Linking

Collagen content and cross-linking are believed to be major determinants of tendon structural integrity and function. Sex and chronic resistance training have been shown to alter tendon function and may also alter the key structural features of tendon. Patellar tendon biopsies were taken from untrained men [ n = 8, 1 repetition maximum (RM) = 53 ± 3 kg], untrained women ( n = 8, 1 RM = 29 ± 2 kg), and resistance-trained (10 ± 1 yr of training) men ( n = 8, 1 RM = 71 ± 6 kg). Biopsies were analyzed for dry mass, collagen content, and collagen cross-linking (hydroxylysylpyridinoline). We hypothesized that these elements of tendon structure would be lower in women than men, whereas chronic resistance training would increase these parameters in men. Tendon dry mass was significantly lower in women than men (343 ± 5 vs. 376 ± 8 μg dry mass/mg tendon wet wt, P < 0.01) and was not influenced by chronic resistance training ( P > 0.05). The lower tendon dry mass in women tended to reduce ( P = 0.08) collagen content per tendon wet weight. Collagen content of the tendon dry mass was not influenced by sex or resistance training ( P > 0.05). Similarly, cross-linking of collagen was unaltered ( P > 0.05) by sex or training. Although sex alters the water content of patellar tendon tissue, any changes in tendon function with sex or chronic resistance training in men do not appear to be explained by alterations in collagen content or cross-linking of collagen within the dry mass component of the tendon.

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