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Minerva Anestesiologica 2001 November;67(11):791-6


language: English

Signal transduction mechanisms and nitric oxide in hypoxic and ischemic human cardiac ventricular cell

Corbucci G. C. *°, Ricchi A. **, Lettieri B. *, Mastronardi P. *

From the University of Cagliari *Institute of Anesthesia and Reanimation *Biomedical Research Group S.I.A.A.R.T.I. **Department of Heart Surgery «Brotzu» Ospedale, Cagliari


Back­ground. ­Nitric ­oxide (NO) ­plays a ­well-­known ­role in reg­u­lat­ing endo­cel­lu­lar adap­tive chang­es to ­acute hypox­ia and ische­mia. The rever­sible inhi­bi­tion of com­plex IV of the mit­o­chon­dri­al res­pir­a­to­ry ­chain ful­fils a cytop­ro­tec­tive func­tion, where­as the pro­gres­sive inhi­bi­tion of com­plex I and II ­reveals the ­onset of irre­ver­sible oxi­da­tive dam­age due to per­sis­tent NO pro­duc­tion in ­response to pro­longed hypox­ia and/or ische­mia. In hypox­ic or ischem­ic ­human myo­car­dial ­cells, ­death may be ­caused by apop­to­sis or necro­sis fol­low­ing the acti­va­tion of the bio­mo­lec­u­lar sig­nal trans­duc­tion mech­a­nisms. The acti­va­tion of ­MAPK (mito­gen-acti­vat­ed pro­tein ­kinase) fol­lowed by ERK (extra­cel­lu­lar reg­u­lat­ed ­kinase) and p21waf is nec­es­sary in ­this ­respect. The myo­car­dial ­cell is ­well ­known for its post­mi­tot­ic ­nature and ­through ­their acti­va­tion ­these kinas­es aim to ­repair DNA dam­aged by oxi­da­tive ­stress in ­order to guar­an­tee the sur­vi­val of the ­cell ­itself. A ­direct cor­re­la­tion has ­been ­found ­between the acti­va­tion of ­these kinas­es and NO pro­duc­tion. It was decid­ed to car­ry out ­this ­study in hypox­ic and ischem­ic ­human ­heart ven­tric­u­lar tis­sue in ­order to con­firm ­this con­nec­tion.
Meth­ods. In 10 ­patients under­go­ing car­diac val­vu­lar replace­ment, ven­tric­u­lar sam­ples ­were col­lect­ed ­before aor­tic clamp­ing, ­after 15 min of ische­mia and ­after 60 min­utes dur­ing ­which the ­patients ­received dos­es of hemat­ic car­di­o­pleg­ic solu­tion at reg­u­lar inter­vals.
­Results. The ­results ­show a rap­id ­increase in NO pro­duc­tion in ­response to ische­mia fol­lowed by a ten­den­cy for lev­els of ­this ele­ment to ­fall. ­MAPK, ERK and p21waf acti­va­tion was par­allel to No pro­duc­tion, irre­spec­tive of the repeat­ed admin­is­tra­tion of hemat­ic car­di­o­pleg­ic solu­tion. The ­heart tis­sue exam­ined 60 min­utes ­after aor­tic clamp­ing ­came ­from a ven­tric­u­lar ­area sub­ject to pre­con­di­tion­ing mech­a­nisms. In ­view of ­this, the ­data ­obtained ­must be ­seen in ­terms of the ­close cor­re­la­tion ­between the mit­o­chon­dri­al ­action ­played by NO and the con­tem­po­rary and con­se­quent acti­va­tion of ­unique sig­nal trans­duc­tion mech­a­nisms.
Con­clu­sions. ­This may ­prove impor­tant to our under­stand­ing of pre­con­di­tion­ing mech­a­nisms involv­ing the myo­car­dial and con­firms the ­role ­played by the ­said kinas­es ­with ­regard to the sur­vi­val of hypox­ic and ischem­ic ­human ­heart tis­sue. ­Although not ­final, ­these deduc­tions may be impor­tant in clin­i­cal and ther­a­peu­tic ­terms for the man­age­ment of crit­i­cal ­patients.

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