The mitochondria-targeting peptide elamipretide diminishes circulating HtrA2 in ST-segment elevation myocardial infarction.

Abstract

BACKGROUND:

The extent of myocardial damage in patients with ST-segment elevation myocardial infarction (STEMI) depends on both the time to reperfusion as well as injury induced by ischaemia-reperfusion resulting in a cascade of cellular and humoral reactions. As a consequence of ischaemia-reperfusion in the heart, the high-temperature requirement serine peptidase 2 (HtrA2) is translocated from the mitochondria to the cytosol, whereupon it induces protease activity-dependent apoptosis mediated via caspases. Myocardial damage induced by reperfusion cannot be monitored due to a current lack in specific biomarkers. We examined the serum level of HtrA2 as a potentially novel biomarker for mitochondrial-induced cardiomyocyte apoptosis.

METHODS:

After informed consent, peripheral blood was obtained from patients (n=19) with first-time acute anterior STEMI after percutaneous coronary intervention. Within this group, 10 of the patients received the mitochondria-targeting peptide elamipretide (phase 2a clinical study EMBRACE (NCT01572909)). Blood was also obtained from a control group of healthy donors (n=16). The serum level of HtrA2 was measured by an enzyme-linked immunosorbent assay (ELISA). In a murine model of myocardial ischaemia-reperfusion injury, HtrA2 was determined in plasma by ELISA after left anterior descending artery occlusion.

RESULTS:

HtrA2 median was significantly increased in patients with STEMI compared to healthy controls 392.4 (240.7-502.8) pg/mL vs. 1805.5 (981.3-2220.1) pg/mL (P⩽0.05). Elamipretide significantly reduced the HtrA2 median serum level after myocardial infarction 1805.5 (981.3-2220.1) pg/mL vs. 496.5 (379.4-703.8) pg/mL (P⩽0.05). Left anterior descending artery occlusion in mice significantly increased HtrA2 mean in plasma (117.4 fg/ml±SEM 28.1 vs. 525.2 fg/ml±SEM 96; P⩽0.05).

CONCLUSION:

Compared to healthy controls, we found significantly increased serum levels of HtrA2 in patients with STEMI. The result was validated in a murine model of myocardial ischaemia-reperfusion injury. In humans the increased serum level was significantly reduced by the mitochondria-targeting peptide elamipretide. In conclusion, HtrA2 is detectable in serum of patients with STEMI and might present a novel biomarker for mitochondrial-induced cardiomyocyte apoptosis. Consequently, HtrA2 may also show promise as a biomarker for the identification of ischaemia-reperfusion injury. However, this must be validated in a lager clinical trial.

• Authors: Marcus Hortmann, Samuel Robinson, Moritz Mohr, Maximillian Mauler, Daniela Stallmann, Jochen Reinöhl, Daniel Duerschmied, Karlheinz Peter, James Carr, C Michael Gibson, Christoph Bode, Ingo Ahrens
• Journal: European heart journal. Acute cardiovascular care (Eur Heart J Acute Cardiovasc Care) Vol. 8 Issue 8 Pg. 695-702 (Dec 2019) ISSN: 2048-8734 [Electronic] England
• PMID: 28534645 (Publication Type: Clinical Trial, Phase II, Comparative Study, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Biomarkers
• Oligopeptides
• Placebos
• arginyl-2,'6'-dimethyltyrosyl-lysyl-phenylalaninamide
• Serine Endopeptidases
• HTRA2 protein, human
• High-Temperature Requirement A Serine Peptidase 2

Topics

• Aged
• Animals
• Apoptosis (drug effects)
• Biomarkers (blood)
• Female
• High-Temperature Requirement A Serine Peptidase 2 (blood, drug effects)
• Humans
• Male
• Mice (blood)
• Middle Aged
• Mitochondria (drug effects, metabolism)
• Myocardial Infarction (blood)
• Myocardium (pathology)
• Myocytes, Cardiac (drug effects, metabolism, pathology)
• Oligopeptides (administration & dosage, metabolism, pharmacology)
• Percutaneous Coronary Intervention (methods)
• Placebos (administration & dosage)
• Prospective Studies
• Reperfusion Injury (blood, complications, veterinary)
• ST Elevation Myocardial Infarction (blood, therapy)
• Serine Endopeptidases (metabolism)