Background:
Thymosin β4 (Tβ4) is a 43 amino acid peptide and has been shown to promote angiogenesis, suppress pro-inflammatory cytokines and protect cardiomyocytes from apoptosis and oxidative stress injury. The Tβ4 cleavage product Ac-SDKP is a tetrapeptide (Acetyl-Ser-Asp-Lys-Pro) that has been shown to inhibit collagen production by fibroblasts and collagen deposition in the LV of rats with hypertension or myocardial infarction. In the setting of chronic heart failure (HF), LV dysfunction and chamber remodeling are associated with interstitial fibrosis, reduced capillary density, cardiomyocyte apoptosis and increased production of reactive oxygen species (ROS).
Hypothesis:
This study tested the hypothesis that protein levels of both Tβ4 and its cleavage product Ac-SDKP are down-regulated in LV myocardium of dogs with advanced chronic HF.
Methods:
LV tissue was obtained from the LV free wall of 6 normal dogs and 6 dogs with chronic HF (LV ejection fraction ~30%) produced by multiple sequential intracoronary microembolizations. Protein levels of Tβ4 and β-actin, as internal control, were determined by Western blotting and bands expressed in densitometric units (du). Levels of Ac-SDKP were determined by ELISA and expressed in ng/mg protein.
Results:
Protein level of β-actin did not change significantly between normal dogs (1.34 ± 0.19 du) and dogs with chronic HF (1.22 ± 0.18 du). Protein level of Tβ4 was significantly lower in LV myocardium of dogs with HF compared to normal dogs (0.36 ± 0.06 vs. 1.64 ± 0.13 du, p<0.05). Similarly, levels of Ac-SDKP were significantly lower in LV myocardium of HF dogs compared to normal dogs (93 ± 9 vs. 155 ± 4 ng/mg protein, p<0.05).
Conclusions:
Protein levels of Tβ4 and its cleavage tetrapeptide Ac-SDKP are markedly down-regulated in LV myocardium dogs with chronic HF. These findings are in-line with the reported increase of pro-inflammatory cytokines, interstitial fibrosis, cardiomyocyte apoptosis, and ROS formation as well as reduced capillary density in the failing LV myocardium of dogs with microembolization-induced HF as well as patients with HF. The findings support the therapeutic targeting of Tβ4 and Ac-SDKP as potential treatment for chronic HF.
Physical training modulates proinflammatory cytokines and soluble fas-soluble fas ligand system in patients with chronic heart failure
