Cardio-Protective Peptide Therapy
- 技术应用
- Treatment of cardiac ischemic reperfusion injury post myocardial infarction
- 详细技术说明
- Short naturally occurring peptide for treatment of cardiac ischemiareperfusion injury
- *Abstract
-
Cardiovascular diseases (CVD) remain the leading causes of deathand disability worldwide, and myocardial infarction (MI) represents the mostcommon underlying mechanism. Importantly, the extent of cardiac dysfunction post-MI is the singlemost powerful predictor of prognosis for CVD, including heart failure anddeath. While great strides have beenmade in reducing ischemic injury post-MI (through more rapid and effectivereperfusion strategies), there is a pressing need for treatments capable ofreducing the damage that occurs as a consequence of reperfusion itself, i.e. ischemia-reperfusioninjury (IRI). Indeed, consensus reviewsof both animal and human studies suggest that as much as 50% of the tissueinjury post-MI is attributable to IRI.The market for therapies against IRI is very large, and yet not a singleagent has regulatory approval for this indication. Supporting the importance of this unmet needis the intense pharmaceutical interest in this space, with ~50 agents atvarious stages of clinical development. Significantly, none of the other agentsunder development appear to intersect with the unique mechanism of action (MOA)identified for GLP-1(28-36).
GLP-1(28-36)is a 9-amino acid C-terminal fragment of the endogenous glucoregulatory hormoneGLP-1(7-36), created by neutral endopeptidase (NEP) 24.11-mediatedcleavage1. The Husain lab was one of thefirst in the world to show that GLP-1(7-36) protects against myocardialischemia reperfusion injury (IRI) in mice, and others have shown similareffects of the parent peptide and its analogues in rat, rabbit, dog, pig andsmall pilot studies in human.Subsequently, they discovered that the smaller peptide GLP-1(28-36) isalso cardioprotective. Using mousemodels of IRI, they found that pre-treatment with GLP-1(28-36) reduces infarctsize and improves cardiac function as compared to saline- or scramblepeptide-treated controls. Using micewith genetic absence of the GLP-1 receptor (Glp1r-/-), they found that theseeffects of GLP-1(28-36) are independent of Glp1r.
Experiments with pharmacological inhibitors suggest that, unlikeGLP-1(7-36), GLP-1(28-36) works through a unique soluble-adenylate cyclase(sAC)-dependent mechanism. This raisesthe prospect of GLP-1(28-36) avoiding any potential undesirable effects ofGlp1r activation during the treatment of IRI, such as on heart rate, bloodpressure, and the sympathetic nervous system, while retaining cardioprotectiveaction. As a relatively short peptide,GLP-1 (28-36) can be produced inexpensively via synthetic methods. As anaturally circulating peptide it also may have reduced immunogenic potential.Concentration-dependent effect of GLP-1 (28-36)on LVDP recovery in isolated hearts undergoing IRI. Isolated heartsfrom male 10-12 wk old wild-type micewere perfused with varying doses of GLP-1(28-36). LVDP recovery, expressed as %of LVDP recorded at end ofreperfusion divided by LVDP prior to ischemia, was significantly increased at a minimum concentrationof 6 nM, n=3-12/group. ****P<0.0001by One-way ANOVA withBonferroni post hoc test.
- *Principal Investigation
-
Dr. Mansoor Husain, University Health Network
- *Publications
- Mundil et al.GLP-1[28-36] Exerts DirectCardioprotective Effects, Activating Pro-Survival Kinases and Soluble AdenylylCyclase Circulation 2012: 126; 21 Suppl. Abstract 13657
- 国家/地区
- 美国
