Abstract
Thymosin beta 4 (Tβ4) was previously shown to reduce infarct size and improve contractile performance in chronic myocardial ischemic injury via two phases of action: an acute phase, just after injury, when Tβ4 preserves ischemic myocardium via antiapoptotic or anti-inflammatory mechanisms; and a chronic phase, when Tβ4 activates the growth of vascular or cardiac progenitor cells. In order to differentiate between the effects of Tβ4 during the acute and during the chronic phases, and also in order to obtain detailed hemodynamic and biomarker data on the effects of Tβ4 treatment suitable for use in clinical studies, we tested Tβ4 in a rat model of chronic myocardial ischemia using two dosing regimens: short term dosing (Tβ4 administered only during the first 3 days following injury), and long term dosing (Tβ4 administered during the first 3 days following injury and also every third day until the end of the study). Tβ4 administered throughout the study reduced infarct size and resulted in significant improvements in hemodynamic performance; however, chamber volumes and ejection fractions were not significantly improved. Tβ4 administered only during the first 3 days following injury tended to reduce infarct size, chamber volumes and improve hemodynamic performance. Plasma biomarkers of myocyte injury were significantly reduced by Tβ4 treatment during the acute injury period, and plasma ANP levels were significantly reduced in both dosing groups. Surprisingly, neither acute nor chronic Tβ4 treatment significantly increased blood vessel density in peri-infarct regions. These results suggest the following: repeated dosing may be required to achieve clinically measureable improvements in cardiac function post-myocardial infarction (MI); improvement in cardiac function may be observed in the absence of a high degree of angiogenesis; and that plasma biomarkers of cardiac function and myocardial injury are sensitive pharmacodynamic biomarkers of the effects of Tβ4.
Highlights
Thymosin beta 4 (Tβ4) is a widely-expressed peptide which has been shown to regulate multiple cellular processes, including cell migration (Malinda et al, 1997; Kobayashi et al, 2002; Sosne et al, 2002; Bock-Marquette et al, 2004), survival (BockMarquette et al, 2004; Sosne et al, 2004) and differentiation (Huang et al, 2006; Philp et al, 2007)
Neither acute nor chronic Tβ4 treatment significantly increased blood vessel density in peri-infarct regions. These results suggest the following: repeated dosing may be required to achieve clinically measureable improvements in cardiac function post-myocardial infarction (MI); improvement in cardiac function may be observed in the absence of a high degree of angiogenesis; and that plasma biomarkers of cardiac function and myocardial injury are sensitive pharmacodynamic biomarkers of the effects of Tβ4
CHRONIC Tβ4 TREATMENT REDUCES INFARCT SIZE AND PRESERVES HEMODYNAMIC FUNCTION IN THE RAT PERMANENT left anterior descending (LAD) OCCLUSION MODEL The first set of experiments tested the effects of Tβ4 in a 28 days, permanent LAD occlusion model of MI in the rat
Summary
Thymosin beta 4 (Tβ4) is a widely-expressed peptide which has been shown to regulate multiple cellular processes, including cell migration (Malinda et al, 1997; Kobayashi et al, 2002; Sosne et al, 2002; Bock-Marquette et al, 2004), survival (BockMarquette et al, 2004; Sosne et al, 2004) and differentiation (Huang et al, 2006; Philp et al, 2007). Bock-Marquette et al reported that Tβ4 treatment initiated just after permanent ligation of the left anterior descending (LAD) coronary artery in mice resulted in improved ejection fraction 14 and 28 days post-surgery; scar volume was reduced 28 days post-surgery (Bock-Marquette et al, 2004). This was reported to be due to preservation of ischemic cardiac myocytes, potentially via activation of the pro-survival Akt pathway. Tβ4 was reported to have qualitatively similar effects in large animals: retroperfusion of Tβ4 increased cardiomyocyte survival in a pig ischemia-reperfusion model of cardiac injury, with concomitant improvements in two measures of cardiac contractility, subendocardial segment shortening and dP/dtmax (Hinkel et al, 2008)
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