Response to Letter Regarding Article, “Biglycan Is Required for Adaptive Remodeling After Myocardial Infarction”
We thank Dr Csont and Dr Ferdinandy for their interest in our work.1 In principle, we agree that it is possible and even likely that more that one factor controls the complex events that accompany myocardial infarction (MI). Nevertheless, we have clearly shown that mortality, frequency of ventricular ruptures, and hemodynamic dysfunction were significantly increased 3 weeks post MI in bgn−/0 mice.1 These findings prove that absence of biglycan impairs remodeling and hemodynamic adaptation after MI in mice. However, we refute the conclusion that biglycan is in general cardioprotective, as suggested by Csont and Ferdinandy.
Neither conclusive differences in proteolytic matrix turnover nor matrix cross-linking were evident in bgn−/0 mice. Instead, post MI in bgn−/0 mice, a striking disturbance of collagen fibril organization was detected by histochemistry and by electron microscopy. Impaired collagen fibrillogenesis is responsible for spontaneous aortic dissections in bgn−/0 mice,2 decreased mechanical strength of skin,3 and deterioration of hemodynamic function after experimental MI in decorin-deficient mice.4 Numerous lines of evidence support our findings of reduced stability of disturbed collagen networks in scars of bgn−/0 mice, which included use of ex vivo measurements, all of which pointed to the fact that the disturbed collagen structure is likely to be the dominant cause of the severe cardiac phenotype of bgn−/0 mice after experimental MI.
In our opinion, it is misleading to draw any functional conclusion concerning the physiological role of biglycan from its regulation through the AT1 receptor, since the AT1 receptor has many other dominant functions post MI. Clearly, then, genetic models such as knock-out and overexpression of biglycan must be used to obtain direct evidence of the role of biglycan (or any other agent) in MI. However, it should also be kept in mind that biglycan is dramatically induced post MI. Therefore, it is debatable whether delineation of physiological functions will be possible exclusively from overexpression studies. Furthermore, as we state in our discussion, the possibility that biglycan could, in fact, have detrimental functions at high tissue concentrations, such as fibrosis and ventricular stiffening, should be considered in future studies using biglycan for therapeutic intervention.
Westermann D, Mersmann J, Melchior A, Freudenberger T, Petrik C, Schaefer L, Lullmann-Rauch R, Lettau O, Jacoby C, Schrader J, Brand-Herrman SM, Young MF, Schultheiss HP, Levkau B, Baba HA, Unger T, Zacharowski K, Tschope C, Fischer JW. Biglycan is required for adaptive remodeling after myocardial infarction. Circulation. 2008; 117: 1269–1276.
Heegaard AM, Corsi A, Danielsen CC, Nielsen KL, Jorgensen HL, Riminucci M, Young MF, Bianco P. Biglycan deficiency causes spontaneous aortic dissection and rupture in mice. Circulation. 2007; 115: 2731–2738.
Danielson KG, Baribault H, Holmes DF, Graham H, Kadler KE, Iozzo RV. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol. 1997; 136: 729–743.