Condiciones sociales y percepciones de los jefes de familia, sobre la problemática

Early studies of the ECM of the body suggested that collagen served only to maintain the structure of organs and was virtually inert (Neuberger et al, 1951). These early decay

studies, measuring the decrease in the specific activity of proline in collagen following a single injection of a radio-labelled amino acid, did not allow for the re-utilisation of amino acids. Later studies using improved methods to accurately measure the turnover of collagen (Laurent, 1982) have shown that collagen turnover is in fact a much more rapid process than had been thought.

1.5.1 Collagen turnover in the normal heart and vasculature

Collagen turnover in the normal heart has not been extensively studied. In the right and left ventricles of rabbits, fractional collagen synthesis rates of 3 %/day and 6 %/day, respectively were found, of which one third is degraded rapidly in both ventricles (Turner

et al, 1986). By comparison, non-collagen protein synthesis was 18 %/day in both

ventricles. Fractional collagen synthesis rates in the rat were 9 %/day at 6 months of age, in comparison with values of 4 %/day and <1 %/day in the lung and skin, respectively (Mays et al, 1991). However, at this age in the heart over 90 % of this collagen is

degraded rapidly, compared to 70 % in the lung and only 14 % in skin. In common with other tissues, such as the lung, collagen synthesis rates have been shown to decrease in the heart with increasing age (Mays, 1990).

Rates of collagen synthesis in the pulmonary artery and aorta of rabbits of 5 %/day and 3 %/day, respectively, were found to be similar to those in the heart (see above) and again demonstrated the dynamic nature of collagen turnover in these tissues. The proportion of collagen degraded rapidly was 50 % in these tissues (Bishop et al, 1990a).

Little information is available concerning the relative rates of synthesis for the different collagen types. In the skin, however, it appears that collagen synthesis is more rapid for type I than III. The half-life for processing type I collagen in rabbit skin has been estimated at 26 minutes (min) compared to 3.9 hours (h) for type HI (Robins, 1979).

1.5.2 Collagen turnover in the hypertrophying heart and in the vasculature during pressure overload

Fibroblasts respond to the stimuli for hypertrophy very rapidly. In the rabbit, 2 days of pulmonary artery banding produced a six-fold increase in fractional synthesis rates in the right ventricle (RV), associated with a fall in the proportion degraded rapidly (although degradation in absolute terms was increased) (Bishop et al, 1994). A four-fold increase in

several other studies demonstrating an increase in types I, III and IV mRNA in response to pressure overload (Chapman et al, 1990, Villareal & Dillmann 1992). These results

suggest that the regulation of collagen deposition occurs, at least in part, at the transcription level. In dogs, 5 days pulmonary artery banding produced an eight-fold increase in collagen synthesis rates in the RV (Bonnin et al, 1981). Using the bleomycin

model (causing acute lung injury and pulmonary hypertension), in which the onset of pressure-overload is more gradual, RV collagen synthesis rates increased by three-fold after 14 days. A fall in RV collagen concentration of 40 % was observed 6 days after the bleomycin administration. This was due to a fall in the total collagen content of the ventricle, indicating a breakdown of part of the existing collagen matrix. An increase in the concentration of free hydroxyproline in these tissues served to support the idea that collagen degradation increases (Turner et al, 1986). Further support for the degradation

of the existing network to accommodate the increase in muscle mass comes from scanning electron microscope studies (Doering et al, 1988). This data also leads to the hypothesis

that the regulation of myocyte and nonmyocyte compartments in the heart may be subject separate regulatory control mechanisms.

Following the three-fold increase in pulmonary artery pressure caused by bleomycin administration, collagen turnover increased in the pulmonary artery from 5 % to 23 % (the hypertensive vessel), but not in the normotensive aorta. A decrease in the proportion of collagen degraded rapidly from 50 % to 8 % was also observed in bleomycin treated animals compared with controls (Bishop et al, 1990a). These results suggest that

increased collagen deposition occurs by both increased synthesis and decreased degradation. As discussed above (section 1.3.3), many studies have demonstrated that, together with SMC hypertrophy, alterations of the structural composition of the arterial

wall characterised by an increase in medial ECM involving principally collagen (Wolinsky, 1971, Wolinsky, 1972, Lee et al, 1983, Brayden et al, 1982), is also a major biochemical

finding in hypertension.

In the development of cardiac hypertrophy, in addition to changes in the amounts of collagen deposited, changes may occur in the relative proportions of the collagen types (discussed above, section 1.3.2). This shift in collagen types may affect the physical

properties of the myocardium (discussed above, section 1.2.1). Few studies have

measured vascular collagen types following the onset of pressure, although no changes in the fibrillar types I and III was observed in the pulmonary artery in the bleomycin model (Bishop etal, 1990a).

1.6 FIBROBLAST PROLIFERATION

Thus far, discussion of the increased collagen deposition in the hypertrophying heart has centred on regulation at sites in the metabolic pathways; with regulation at the level of transcription, translation and also via alterations in the amount of collagen entering the degradative pathways. Regarding increases in collagen synthesis, the increase may occur via an increase in production per fibroblast or an increase in the number of fibroblasts, or both (Figure 1.2). An increase in collagen synthesis before an increase in DNA content in the bleomycin model (Turner et al, 1986) is evidence that an increase in synthesis in

existing fibroblasts may occur prior to an increase in fibroblast number. Several other studies also support this hypothesis (Grove et al, 1969, Morkin & Ashford, 1968 and

Skosey et al, 1972,). van Krimpen et «/ (1991a) demonstrated a transient rise in 5-bromo-

2'-deoxyUridine (brdU) incorporation after induction of MI in the rat. DNA synthesis was localised mainly in the cardiac interstitium. Concomitantly, a sustained increase in cardiac

Figure 1.2: Schematic representation showing the mechanisms o f increased collagen

deposition in cardiac hypertrophy accompanying pressure overload and possible

regulatory factors.

/

PRESSURE

OVERLOAD

AUTOCRINE/PARACRINE

GROWTH FACTORS

eg.PDGF,TGF-p,An

\

CIRCULATING FACTORS

eg. All, thrombin, fibrin(ogen)

cleavage products

\

collagen content was found. However, in the study of Skosey et al (1972), maximum

incorporation of labelled proline into collagen preceded the peak of DNA production, suggesting an increase in collagen production per fibroblast, at least in the early stages of hypertrophy. Taken together, the data suggest that enhanced collagen production in the heart is increased by both mechanisms.

1.7 FACTORS REGULATING THE DEVEOPMENT OF CARDIAC