C1‐esterase inhibitor and a novel peptide inhibitor improve contractile function in reperfused skeletal muscle

Abstract

To determine the role of inhibition of complement activation in the contractile function of skeletal muscle ischemia-reperfusion (I/R) injury, the rat extensor digitorum longus (EDL) muscles underwent 3 h ischemia and received human C1-esterase inhibitor (C1-INH, 100 IU/kg), a synthetic C1q A chain peptide with a similar inhibitory effect on activated C1 (peptide, 5 mg/kg), or human serum albumin control. Results showed a significant overall increase in tetanic contractile forces of the reperfused EDL in both C1-INH and peptide groups compared to controls. Maximum improvement occurred with peptide treatment at 120-Hz stimulation, with an increase in force from 38 +/- 4% of normal in controls to 52 +/- 4% in peptide-treated rats. There were no significant differences between C1-INH and peptide groups. Plasma C3 and C4 activities were significantly increased in both treated groups, suggesting inhibition of complement activation. Our results suggest that complement activation is involved in I/R injury, and inhibition of complement activation may therefore represent a potential therapeutic approach to reducing or preventing I/R injury.

Transient Limb Ischemia Alters Serum Protein Expression in Healthy Volunteers: Complement C3 and Vitronectin May Be Involved in Organ Protection Induced by Remote Ischemic Preconditioning

“…Inhibition of the complement system can improve the outcome of IR injury [23, 24]. In a rabbit model, Tanhehco and co-workers observed that ischemic and chemical preconditioning inhibited the upregulation of complement C1q, C1r, C3, C8, and C9 mRNA expression and the complement C3 and membrane attack complex protein expression caused by IR injury both in vivo and in isolated heart in rabbits [25, 26].…”

C1q: Its Functions within the Innate and Adaptive Immune Responses and its Role in Lupus Autoimmunity

“…Parameters of SLE clinical disease activity improved upon removing from the circulation molecules that bind to and consume C1q. It has been suggested that some of the injurious results of human complement activation such as ischemia-reperfusion muscle injury can be blocked by a synthetic peptide corresponding to the 14-26 amino acids of the collagenous stalk domain of C1qA (C1qA 14-26 peptide) that has been shown to inhibit classical pathway activation (Toomayan et al, 2003). Presumably, this C1qA 14-26 peptide has an inhibitory action on complement activation similar to that of C1-INH, which is related to its net cationic charge (Bradley et al, 1999).…”

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