ABC | Volume 115, Nº1, July 2020

Original Article Silva-Bertani et al. Mechanism of decreased heart collagen I in obesity Arq Bras Cardiol. 2020; 115(1):61-70 The changes in myocardial collagen may result from an elevation of the synthesis or decreased degradation. The data from this study showed that the degradation of collagen type I may have prevailed in obese rats, as there was a significant association between reduced collagen type I and increased MMP-2 activity. Although some studies show that the increase in MMP-2 activity enhances collagen synthesis, 40 most information in the literature indicates the opposite behavior, i.e., the increase in MMP-2 activity promotes the degradation of collagen type I. 5,39,41 Although Martínez-Martínez et al. 39 and Zibadi et al. 14 have found that leptin reduced the MMP-2 activity in vitro , other studies have shown that leptin increases MMP-2 activity, 5,15,16 and our results further support this latest finding. Thus, the elevation of MMP-2 may have been consequent to increased cardiac leptin, because there was a close association between these two variables, although these findings do not necessarily reflect a cause-and-effect relationship. Nevertheless, several studies have reported a direct relation between leptin and MMP-2 activity in cardiomyocytes. 5,15,16 Despite the fact that increased MMP activity is associated with elevated cardiac leptin, another modifying factor of this enzyme is the behavior of TIMP. The results of the present study showed a decrease in TIMP-1 and TIMP-2 protein levels in obese animals, which may have influenced the increase of MMP-2, given that there was a significant association between MMP-2 and TIMP-1 and TIMP-2. The reduced TIMP-1 may be related to the increase in leptin, as there was a significant association between these variables. This finding is consistent with Schram et al., who found a substantial reduction in TIMP-1 mRNA expression after the elevation of leptin concentrations in cultured cardiac cells. 15 To our knowledge, this is the first study that evaluated the association between collagen type I, leptin, MMP-2, and TIMP-1 and TIMP-2 in the myocardium of obese animals fed an unsaturated high-fat diet. However, further analyses are required to confirm the cause-and-effect relationship. Conclusion The findings confirmed the hypothesis that the reduction in collagen type I is associated with increased MMP-2 activity, which is in turn linked to an elevation of leptin in the myocardium of obese rats. This study allowed for evaluation of mediators involved in cardiac remodeling, which can trigger impaired heart function in obesity. The identification of these deleterious factors may enable possible therapeutic targets. Author contributions Conception and design of the research: Silva-Bertani DCT, Padovani CR, Cicogna AC; Acquisition of data: Silva-Bertani Figure 3 – Relation between active (active and intermediate active) and inactive MMP-2 in control and obese rats (n = 6 per group). Inactive MMP-2 = 72 kDa and active MMP-2 = 64 kDa. Data expressed as mean ± standard deviation. Student’s t test. *: p < 0.05. Table 3 – Linear association between cardiac variables Association Coefficient of correlation p value Collagen I × MMP-2 −0.723 0.008 MMP-2 × Leptin 0.766 0.004 MMP-2 × TIMP-1 −0.815 0.001 MMP-2 × TIMP-2 −0.597 0.040 TIMP-1 × Leptin −0.656 0.020 TIMP-2 × Leptin −0.273 0.390 MMP: metalloproteinase; TIMP: tissue inhibitor of metalloproteinases. Pearson’s correlation test. Control, n = 6 and obese, n = 6. 67