Warning: file_get_contents(https://eutils.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&id=28369703
&cmd=llinks): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 215
The gap junction modifier ZP1609 decreases cardiomyocyte hypercontracture
following ischaemia/reperfusion independent from mitochondrial connexin 43
#MMPMID28369703
Boengler K
; Bulic M
; Schreckenberg R
; Schlüter KD
; Schulz R
Br J Pharmacol
2017[Jul]; 174
(13
): 2060-2073
PMID28369703
show ga
BACKGROUND AND PURPOSE: Dysregulation of gap junction-mediated cell coupling
contributes to development of arrhythmias and myocardial damage after
ischaemia/reperfusion (I/R). Connexin 43 (Cx43) is present at ventricular gap
junctions and also in the mitochondria of cardiomyocytes. The dipeptide (2S,
4R)-1-(2-aminoacetyl)-4-benzamidopyrrolidine-2-carboxylic acid (ZP1609) has
antiarrhythmic properties and reduces infarct size when given at reperfusion.
However, it is unclear, whether ZP1609 targets Cx43-containing mitochondria and
affects cardiomyocyte hypercontracture following I/R. EXPERIMENTAL APPROACH: We
studied the effects of ZP1609 on the function of murine sub-sarcolemmal
mitochondria (SSM, containing Cx43) and interfibrillar mitochondria (IFM, lacking
Cx43). Murine isolated cardiomyocytes were subjected to simulated I/R without and
with ZP1609 (applied during I/R or at the onset of reperfusion only), and the
number of cardiomyocytes undergoing hypercontracture was quantified. Biochemical
pathways targeted by ZP1609 in cardiomyocytes were analysed. KEY RESULTS: ZP1609
inhibited ADP-stimulated respiration and ATP production in SSM and IFM. ROS
formation and calcium retention capacities in SSM and IFM were not affected by
ZP1609, whereas potassium uptake was enhanced in IFM. The number of rod-shaped
cardiomyocytes was increased by ZP1609 (10 ?M) when administered either during
I/R or reperfusion. ZP1609 altered the phosphorylation of proteins contributing
to the protection against I/R injury. CONCLUSIONS AND IMPLICATIONS: ZP1609
reduced mitochondrial respiration and ATP production, but enhanced potassium
uptake of IFM. Additionally, ZP1609 reduced the extent of cardiomyocytes
undergoing hypercontracture following I/R. The protective effect was independent
of mitochondrial Cx43, as ZP1609 exerts its effects in Cx43-containing SSM and
Cx43-lacking IFM.
free
free
free
