Degradation of the α-Carboxyl Terminus 11 Peptide: In Vivo and Ex Vivo Impacts of Time, Temperature, Inhibitors, and Gender in Rat
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE(2024)
Abstract
In previous research, a synthetic alpha-carboxyl terminus 1 (alpha CT1) peptide derived from connexin 43 (Cx43) and its variant (alpha CT11) showed beneficial effects in an ex vivo ischemia-reperfusion (I/R) heart injury model in mouse. In an in vivo mouse model of cryo-induced ventricular injury, alpha CT1 released from adhesive cardiac patches reduced Cx43 remodeling and arrhythmias, as well as maintained cardiac conduction. Whether intravenous injection of alpha CT1 or alpha CT11 produces similar outcomes has not been investigated. Given the possibility of peptide degradation in plasma, this study utilized in vivo I/R cardiac injury and ex vivo blood plasma models to examine factors that may limit the therapeutic potential of peptide therapeutics in vivo. Following tail vein administration of alpha CT11 (100 mu M) in blood, no effect on I/R infarct size was observed in adult rat hearts on day 1 (D1) and day 28 (D28) after injury (p > 0.05). There was also no difference in the echocardiographic ejection fraction (EF%) between the control and the alpha CT11 groups (p > 0.05). Surprisingly, alpha CT11 in blood plasma collected from these rats was undetectable within similar to 10 min after tail vein injection. To investigate factors that may modulate alpha CT11 degradation in blood, alpha CT11 was directly added to blood plasma isolated from normal rats without I/R and peptide levels were measured under different experimental conditions. Consistent with in vivo observations, significant alpha CT11 degradation occurred in plasma within 10 min at 22 and 37 degrees C and was nearly undetectable by 30 min. These responses were reduced by the addition of protease/phosphatase (PTase/PPTase) inhibitors to the isolated plasma. Interestingly, no significant differences in alpha CT11 degradation in plasma were noted between male and female rats. We conclude that fast degradation of alpha CT11 is likely the reason that no beneficial effects were observed in the in vivo I/R model and inhibition or shielding from PTase/PPTase activity may be a strategy that will assist with the viability of peptide therapeutics.
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Key words
therapeutic peptide,alpha CT11,degradation,enzymatic inhibitors,rat,mass spectrometry
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