Leptin regulates MMP-2, TIMP-1 and collagen synthesis via p38 MAPK in HL-1 murine cardiomyocytes

Abstract

Abbreviations used: AP-1 -activator protein-1; ATF-2 -activating transcription factor-2; ECM -extracellular matrix; HF-heart failure; LV -left ventricular; MAPK -mitogen activated protein kinase; MMP -matrix metalloproteinase; mRNA-messenger ribonucleic acid; PBS -phosphate buffered saline; PCR -polymerase chain reaction; TIMP-tissue inhibitor of metalloproteinase Abstract: A clear association between obesity and heart failure exists and a significant role for leptin, the product of the obese gene, has been suggested. One aspect of myocardial remodeling which characterizes heart failure is a disruption in the balance of extracellular matrix synthesis and degradation. Here we investigated the effects of leptin on matrix metalloproteinase (MMP) activity, tissue inhibitor of metalloproteinase (TIMP) expression, as well as collagen synthesis in HL-1 cardiac muscle cells. Gelatin zymographic analysis of MMP activity in conditioned media showed that leptin enhanced MMP-2 activity in a dose-and time-dependent manner. Leptin is known to stimulate phosphorylation of p38 MAPK in cardiac cells and utilization of the p38 MAPK inhibitor, SB203580, demonstrated that this kinase also plays a role in regulating several extracellular matrix components, such that inhibition of p38 MAPK signaling prevented the leptin-induced increase in MMP-2 activation. We also observed that leptin enhanced collagen synthesis determined by both proline incorporation and picrosirius red staining of conditioned media. Pro-collagen type-I and pro-collagen type-III expression, measured by real-time PCR and Western blotting were also increased by leptin, effects which were again attenuated by SB203580. In summary, these results demonstrate the potential for leptin to play a role in mediating myocardial ECM remodeling and that the p38 MAPK pathway plays an important role in mediating these effects.

Matrix metalloproteinase inhibition impairs murine adipose tissue development independently of leptin

“…Tolylsam treatment was associated with significantly reduced levels of leptin, which correlate positively with body fat mass and adipocyte size [5,18]. Leptin contributes to enhanced MMP-2 levels in different cell types [7][8][9][10][11][12]. In vascular smooth muscle cells leptin induces MMP-2 expression via protein kinase C-dependent activation of NAD(P)H oxidase with subsequent activation of the ERK1/2/NF-kappa B pathways [8].…”

“…It is well known that leptin, the product of the ob gene, is an endocrine hormone that regulates adipose tissue mass. In addition several in vitro and in vivo studies have revealed that leptin induces MMP-2 expression and activity [7][8][9][10][11][12]. This raises the question whether the marked effect of gelatinase inhibition by Tolylsam in a murine model of nutritionally induced obesity may be due not only to direct MMP inhibition, but also to an indirect effect via reduction of leptin and associated decrease in MMP-2 levels.…”

Leptin’s regulation of obesity-induced cardiac extracellular matrix remodeling

“…Leptin treatment in human pediatric cardiomyocytes resulted in increased gene expression of MMP-2 and collagen type III and IV, while suppressing collagen type I mRNA, without affecting total collagen synthesis [10]. It also regulated MMP-2, TIMP-1, and collagen synthesis via p38 MAPK pathway in HL-1 murine cardiomyocytes [11]. The pro-fibrotic effects of leptin in hepatic and renal tissues have been extensively investigated in rodent-induced fibrosis models.…”

Effects of duodenal-jejunal bypass on structure of diaphragm in western diet obese rats

“…According to Hu et al 11 , moderately obese rats submitted to a high calorie diet have a high concentration of leptin. This hormone enhances the activity of the metalloproteinases MMP-229 29 and the mRNA expression of MMP-9 30 , enzymes responsible for collagen degradation. As the percentage of collagen in the diaphragm muscle was similar in the WD DJB and WD SHAM groups, it is suggested that the continued use of the cafeteria diet and the maintenance of post-DJB body weight maintained the leptin concentration and activity of matrix metalloproteinases high, leading to increased degradation of collagen in relation to its synthesis.…”