Prostacyclin Release by Rat Cardiac Fibroblasts

Abstract

Cardiac fibroblasts, as the source of extracellular matrix for the left ventricle, subserve important functions to cardiac remodeling and fibrotic development following myocardial infarction or with pressure-overload cardiac hypertrophy. The fibroblast may be the target cell for angiotensin-converting enzyme inhibitors (ACEI) that are cardioprotective and reverse collagen deposition and remodeling but whose mechanisms of action remain controversial. Because we previously documented phenotypic differences between cardiac fibroblasts from the spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) left ventricle, the present study evaluated whether phenotypic differences also exist in the release of endogenous arachidonic acid metabolites or in the activation of phospholipase D, and the importance of observed differences to the formation of collagen and the mechanism of action of ACEI. The experimental design compared endogenous sources of arachidonic acid with exogenous prelabeling of cells. Angiotensin II stimulated greater arachidonic acid release than bradykinin, and WKY cells were more responsive than SHR. The major prostanoid formed by cardiac fibroblasts was prostaglandin I2 (PGI2), with more prostacyclin production by WKY cells than SHR cells both under nonstimulated conditions and in response to angiotensin II or bradykinin. Beraprost, a PGI2 analogue, was shown to decrease growth rate and DNA synthesis of fibroblasts and to inhibit mRNA expression for collagen types I and III, with SHR cells being less responsive to beraprost than WKY cells. These results potentially implicate eicosanoid metabolism, particularly PGI2, in collagen formation, fibrotic development, and cardiac remodeling, and they imply that the SHR genetic hypertension model may be predisposed to excess cardiac fibrosis.

Targeted Deletion of Angiotensin II Type 2 Receptor Caused Cardiac Rupture After Acute Myocardial Infarction

“…22 PGE 2 inhibits collagen production by several mechanisms, including reduction in the uptake of proline, inhibition of collagen gene expression, and a decrease in collagen types I and III mRNA levels. 23,24 Furthermore, PGF 2␣ has been shown to be released from cells after experimental infarction and to stimulate hypertrophic growth. 25 It was recently reported that the pharmacological blockade of AT 2 potentiated the Ang II-induced production of PGE 2 .…”

Effect of Long-term Administration of a Prostacyclin Analogue (Beraprost Sodium) on Myocardial Fibrosis in Dahl Rats

“…In addition, the changes in myocardial structure inhibit myocardial diastolic and systolic function, resulting in cardiac dysfunction [26,27]. The effects of BPS, such as coronary circulation improvement, myocardial and vascular protection [19] and its anti-fibrosis effect on myocardial interstitium [30], have been demonstrated previously. However, the effects of BPS on hemodynamics, cardiac function and myocardial contractility in patients in the hypertrophic phase have not been clarified.…”

Augmented Cardiac Hypertrophy in Response to Pressure Overload in Mice Lacking the Prostaglandin I 2 Receptor

“…These include inhibitory effects of PGI 2 and its analogue on angiotensin II-induced hypertrophy in cultured cardiomyocytes 12 and their inhibitory effects on proliferation and collagen synthesis in cultured cardiac fibroblasts. 13 In addition, synthesis of PGE 2 and PGI 2 has been reported to be elevated in the hypertrophied and failing heart 14,15 along with an upregulation of cyclooxygenase (COX)-2. 16 The hypertrophic effect of exogenously administered PGF 2 ␣ on cardiomyocytes has also been reported.…”