Regional cardiac prostaglandin release during myocardial ischemia in anesthetized dogs.

Abstract

SUMMARY Cardiac prostaglandin release was studied in closedchest dogs during acute coronary occlusion. Aortic and coronary sinus blood was obtained before, and at intervals after, balloon occlusion of the left anterior descending artery in seven dogs. Samples were assayed for prostaglandins F, E, and A by radioimmunoassay. All dogs demonstrated prostaglandin F release. Mean ± SE postocclusion aortic levels were 0.26 ± 0.01 ng /ml; coronary sinus levels were 0.67 ± 0.01 ng/ml [P < 0.001). In six dogs, prostaglandin E also was released. Mean postocclusion aortic levels were 0.24 ± 0.01 ng/ml; coronary sinus, 0.44 ± 0.01 ng/ml (P < 0.001). There was no release of prostaglandin A. To examine the site of prostaglandin release, simultaneous samples from the aorta, the coronary sinus, and the great cardiac vein were obtained before and after left circumflex artery occlusion in six additional studies. The great cardiac vein drained effluent from nonischemic myocardium, whereas the coronary sinus drainage included blood from both ischemic and nonischemic zones. All six dogs demonstrated prostaglandin F release from the ischemic region. Mean postocclusion aortic prostaglandin F was 0.32 ± 0.01 ng/ml. Coronary sinus prostaglandin F was 1.69 ± 0.03 ng/ml (P < 0.001), whereas the great cardiac vein level remained at 0.34 ± 0.01 ng/ml (P > 0.05). Prostaglandin E was released from both ischemic and nonischemic regions. Mean aortic prostaglandin E was 0.21 ± 0.01 ng/ml; great cardiac vein, 0.55 ± 0.02 ng/ml (P < 0.001); and coronary sinus, 1.07 ± 0.04 ng/ml (P < 0.001). These results have led us to conclude that the different local availability of prostaglandins E and F may influence the cardiac response to ischemia.

Prostaglandin F2.ALPHA. Inhibits SERCA2 Gene Transcription Through an Induction of Egr-1 in Cultured Neonatal Rat Cardiac Myocytes

“…We made several major observations: (i) PGF 2α inhibited SERCA2 gene expression at the transcriptional level in cultured neonatal rat cardiac myocytes, (ii) a sequence downstream of -282, which contains multiple Egr-1, Sp1, and AP2 binding motifs, was responsive to PGF 2α , (iii) antisense oligonucleotide for transcription factor Egr-1 prevented the decrease in SERCA2 gene expression by PGF 2α , and (iv) the effect of PGF 2α was mediated through Ras, Rac, and p38 MAPK-dependent pathways. While previous studies have focused upon the inducible effect of PGF 2α on cardiac genes such as myosin light chain-2, atrial natriuretic peptide (ANP), and skeletal α-actin genes, 9,13) the results of the present study indicate that the SERCA2 gene is one of the primary target genes of PGF 2α .…”

“…[6][7][8] PGF 2α is released from cells of the myocardium subsequent to experimental infarction 9,10) and pressure overload. 11) In vitro experiments showed that cultured rat ventricular myocytes subjected to short periods of hypoxia demonstrated a 6-fold increase in PGF 2α production compared with normoxic control myocytes.…”

“…12) Exogenously administered PGF 2α stimulates hypertrophy of neonatal rat cardiac myocytes. 9,13,14) Thus, PGF 2α is produced from cardiac myocytes in response to a variety of mechanical and chemical stimuli, which make them possible candidates for mediating responses to cardiac muscle stress. However, there is no compelling evidence of signaling mechanisms being involved in PGF 2α regulation of SERCA2 gene expression during cardiac hypertrophy.…”

Reperfusion after acute coronary occlusion in dogs impairs endothelium-dependent relaxation to acetylcholine and augments contractile reactivity in vitro.

“…Meclofenamate restored vascular reactivity to normal, implicating a potential role for ischemia-related vasodilator prostaglandin production (29,30). Although meclofenamate also shifted the control dose response curve leftward, the magnitude of this increase in reactivity was considerably less than that in ischemic rings.…”

SERCA2a: its role in the development of heart failure and as a potential therapeutic target

“…98 Prostaglandin-F2 (PGF2) is a vasoconstrictor involved in inflammatory response that is produced in the myocardium subsequent to infarction or pressure overload. [99][100][101] It was shown that PGF2 stimulates hypertrophic growth of neonatal rat cardiac myocytes, including downregulation of SERCA2a. Interestingly, PGF2 increased early growth response protein 1 (Egr-1) expression and overexpression of Egr-1 decreased transcription of the proximal SERCA2 gene promoter.…”