Abstract
Search for new cardioprotective therapies is of great importance since no cardioprotective drugs are available on the market. In line with this need, several natural biomolecules have been extensively tested for their potential cardioprotective effects. Previously, we have shown that biglycan, a member of a diverse group of small leucine-rich proteoglycans, enhanced the expression of cardioprotective genes and decreased ischemia/reperfusion-induced cardiomyocyte death via a TLR-4 dependent mechanism. Therefore, in the present study we aimed to test whether decorin, a small leucine-rich proteoglycan closely related to biglycan, could exert cardiocytoprotection and to reveal possible downstream signaling pathways. Methods: Primary cardiomyocytes isolated from neonatal and adult rat hearts were treated with 0 (Vehicle), 1, 3, 10, 30 and 100 nM decorin as 20 h pretreatment and maintained throughout simulated ischemia and reperfusion (SI/R). In separate experiments, to test the mechanism of decorin-induced cardio protection, 3 nM decorin was applied in combination with inhibitors of known survival pathways, that is, the NOS inhibitor L-NAME, the PKG inhibitor KT-5823 and the TLR-4 inhibitor TAK-242, respectively. mRNA expression changes were measured after SI/R injury. Results: Cell viability of both neonatal and adult cardiomyocytes was significantly decreased due to SI/R injury. Decorin at 1, 3 and 10 nM concentrations significantly increased the survival of both neonatal and adult myocytes after SI/R. At 3nM (the most pronounced protective concentration), it had no effect on apoptotic rate of neonatal cardiac myocytes. No one of the inhibitors of survival pathways (L-NAME, KT-5823, TAK-242) influenced the cardiocytoprotective effect of decorin. MYND-type containing 19 (Zmynd19) and eukaryotic translation initiation factor 4E nuclear import factor 1 (Eif4enif1) were significantly upregulated due to the decorin treatment. In conclusion, this is the first demonstration that decorin exerts a direct cardiocytoprotective effect possibly independent of NO-cGMP-PKG and TLR-4 dependent survival signaling.
Highlights
There is an unmet clinical need for cardioprotective therapies against myocardial ischemiareperfusion (I/R) injury [1,2]
We have shown that exogenous administration of biglycan, which denotes a diverse group of small leucine-rich proteoglycan family, protects myocardial cells from simulated ischemia and reperfusion (SI/R) injury via Toll-like receptor-4-mediated mechanisms involving activation of survival kinases such as ERK, JNK and p38 MAP kinases and increased nitric oxide (NO) production [5,6]
Treatment of the Neonatal Rat Cardiac Myocytes (NRCMs) with different concentrations of decorin for 4 + 2 h in normoxic conditions showed that decorin applied in 3 nM and 10 nM concentrations significantly increased cell viability of NRCMs while 1 nM, 30 nM and 100 nM concentrations has not changed when compared to the vehicle-treated normoxic group (Figure 1a)
Summary
There is an unmet clinical need for cardioprotective therapies against myocardial ischemiareperfusion (I/R) injury [1,2]. Novel potential cardioprotective therapies are much sought for. Proteoglycans are potential cardioprotective macromolecules of the extracellular matrix (ECM) which have been shown to play important roles in the ECM such as cell adhesion, deposition of collagens, activation of cytokines and growth factors or matrix assembly [3,4]. We have shown that exogenous administration of biglycan, which denotes a diverse group of small leucine-rich proteoglycan family, protects myocardial cells from simulated ischemia and reperfusion (SI/R) injury via Toll-like receptor-4-mediated mechanisms involving activation of survival kinases such as ERK, JNK and p38 MAP kinases and increased nitric oxide (NO) production [5,6].
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