Universität zu Köln

Kaiser, Annette, Heiss, Kirsten, Mueller, Ann-Kristin, Fimmers, Rolf, Matthes, Jan and Njuguna, James Thujon (2020). Inhibition of EIF-5A prevents apoptosis in human cardiomyocytes after malaria infection. Amino Acids, 52 (5). S. 693 - 711. WIEN: SPRINGER WIEN. ISSN 1438-2199

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Abstract

In this study, a determination of Troponin I and creatine kinase activity in whole-blood samples in a cohort of 100 small infants in the age of 2-5 years from Uganda with complicated Plasmodium falciparum malaria suggests the prevalence of cardiac symptoms in comparison to non-infected, healthy patients. Troponin I and creatine kinase activity increased during infection. Different reports showed that complicated malaria coincides with hypoxia in children. The obtained clinical data prompted us to further elucidate the underlying regulatory mechanisms of cardiac involvement in human cardiac ventricular myocytes. Complicated malaria is the most common clinical presentation and might induce cardiac impairment by hypoxia. Eukaryotic initiation factor 5A (eIF-5A) is involved in hypoxia induced factor (HIF-1 alpha) expression. EIF-5A is a protein posttranslationally modified by hypusination involving catalysis of the two enzymes deoxyhypusine synthase (DHS) and deoxyhypusine hydroxylase. Treatment of human cardiomyocytes with GC7, an inhibitor of DHS, catalyzing the first step in hypusine biosynthesis led to a decrease in proinflammatory and proapoptotic myocardial caspase-1 activity in comparison to untreated cardiomyocytes. This effect was even more pronounced after co-administration of GC7 and GPI from P. falciparum simulating the pathology of severe malaria. Moreover, in comparison to untreated and GC7-treated cardiomyocytes, co-administration of GC7 and GPI significantly decreased the release of cytochrome C and lactate from damaged mitochondria. In sum, coadministration of GC7 prevented cardiac damage driven by hypoxia in vitro. Our approach demonstrates the potential of the pharmacological inhibitor GC7 to ameliorate apoptosis in cardiomyocytes in an in vitro model simulating severe malaria. This regulatory mechanism is based on blocking EIF-5A hypusination.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kaiser, Annette UNSPECIFIED UNSPECIFIED UNSPECIFIED Heiss, Kirsten UNSPECIFIED UNSPECIFIED UNSPECIFIED Mueller, Ann-Kristin UNSPECIFIED UNSPECIFIED UNSPECIFIED Fimmers, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED Matthes, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Njuguna, James Thujon UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-334450
DOI:	10.1007/s00726-020-02843-2
Journal or Publication Title:	Amino Acids
Volume:	52
Number:	5
Page Range:	S. 693 - 711
Date:	2020
Publisher:	SPRINGER WIEN
Place of Publication:	WIEN
ISSN:	1438-2199
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INITIATION-FACTOR 5A; DEOXYHYPUSINE SYNTHASE; PROMOTES TRANSLATION; FALCIPARUM-MALARIA; MYOCARDIAL DAMAGE; CRYSTAL-STRUCTURE; CREATINE-KINASE; HUMAN SERUM; TROPONIN-I; DEATH Multiple languages Biochemistry & Molecular Biology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/33445