Unit:
Τομέας ΦΑΡΜΑΚΕΥΤΙΚΗΣ ΧΗΜΕΙΑΣLibrary of the School of Science
Author:
Μπιμπλή Σοφία-Ίρις
Dissertation committee:
Ανδρεάδου Ιωάννα Επίκ.Καθηγήτρια (επιβλέπουσα), Παπαπετρόπουλος Ανδρέας Καθηγητής, Ηλιοδρομίτης Ευστάθιος Καθηγητής
Original Title:
Novel insights into the role of nitric oxide and hydrogen sulfide in myocardial protection.
Translated title:
Καινοτόμα δεδομένα του ρόλου του μονοξειδίου του αζώτου και του υδροθείου στην μυοκαρδιακή προστασία.
Summary:
Aim: We sought to evaluate the role and the underlying molecular mechanisms of
endogenous produced or exogenous administrated gasotransmitters, NO and H2S, on
i) the pathophysiology of myocardial ischemia (I)- reperfusion (R) injury; ii)
PostC mimicking effects in myocardial infarction and iii) their physiological
role in cigarette smoking (CS). The aims were assessed by performing four
separate experimental studies.
Methods and Results: In the first study oxidative stress injury by H2O2 in
cardiomyocytes or in vivo myocardial I-R injury increased PYK2 activity and
eNOS phosphorylation on both the inhibitory site Y656 and on the activator site
S1176. Activity assays demonstrated that Y657 exerts a dominant effect over
S1176. Pharmacological blockade of PYK2 alleviated eNOS inhibition and reduced
myocardial infarct size in wild-type, but not in eNOS KO mice.
In the second and third study low dose IV NTG and NaHS reduced infarct size in
anesthetized male rabbits without affecting haemodynamics. However differences
were detected in the downstream pathways. On one hand NTG’s protection was
abolished by PI3K and NOS inhibition and NTG had no effect on infarct size in
eNOS KO mice. Moreover, NTG failed to increase cardiac cGMP levels while PKG
inhibition did not reverse NTG’s infarct limiting effects. Mechanistically, NTG
protected through a CypD-dependent manner as it failed to confer additional
protection in hearts from CypD KO mice. Interestingly, NTG minimized
nitro-oxidative stress due to an eNOS mediated mechanism. On the other hand NOS
inhibition did not alter the effect of NaHS in rabbit hearts; however, genetic
or pharmacological inhibition of eNOS abolished the infarct-limiting effect of
NaHS in mice. NaHS increased cardiac cGMP levels and PKG inhibition abrogated
its protective effects. In addition, it enhanced phosphorylation of
phospholamban (PLN), in a PKG-dependent manner and did not exert
cardioprotection in PLN KO mice.
In the fourth study exposure of mice to CS increased blood pressure and up
regulated the NOS/sGC/cGMP pathway whilst decreased H2S generating enzymes
expression. Exposure to CS did not increase the infarction compared to the room
air (RA)-exposed group. PreC but not PostC application was beneficial for both
CS and RA vs non-conditioned animals. PreC preserved its effects in mice
exposed to CS, as it does not affect the cardioprotective signaling; in
contrast to PostC.
Conclusions: i) PYK2 is a pivotal regulator of eNOS function in the
pathophysiology of myocardial infarction; ii) Exogenous administration of NO
and H2S donors reduces myocardial infarct size. The two gaseous molecules act
different in the upstream pathways, but both preserve mitochondrial integrity
and rescue cardiomyocytes from death and iii) CS is a new comorbidity that
blunts PostC beneficial effects in the myocardium due to impaired activation of
the Akt/eNOS/cGMP axis that occurs in parallel to enhanced oxidative stress
Keywords:
Nitroglycerin, Hydrogen sulfide, Myocardial Infarction, Cigarette smoking, Ischemia-reperfusion injury
Number of index pages:
8-10
Number of references:
431
