Selective Upregulation of Cardiac Endothelin System in Patients With Ischemic but Not Idiopathic Dilated Cardiomyopathy

Abstract

Abstract-Only scarce information is available on the activity and modifications of the cardiac endothelin (ET)-1 system in heart failure due to ischemic (ICM) or idiopathic dilated (DCM) cardiomyopathy. The activity of the ET-1 system was investigated by measuring cardiac ET-1 and big ET-1 formation and quantifying cardiac mRNA for prepro-ET-1 (ppET-1), ET-converting enzyme-1, and ET A and ET B receptors both in myocardium and in isolated myocytes using Northern blot, reverse transcription-polymerase chain reaction, and in situ hybridization in 22 patients with DCM and 20 with ICM who underwent cardiac transplantation and in 7 potential heart transplant donors (nonfailing hearts). Notwithstanding a similar increase of plasma ET-1 in the 2 groups, cardiac ET formation, mRNA levels for ppET-1, and ET A and ET B receptors were higher on both the myocardium and isolated myocytes from ICM than on those from DCM hearts (PϽ0.001 for all). ppET-1 and ET-converting enzyme-1 mRNAs were expressed on myocytes and endothelial and interstitial cells in ICM, whereas in DCM and nonfailing hearts they were mainly expressed on nonmyocyte cells. In both ICM and DCM, the ET A mRNA signal was expressed on both myocytes and nonmyocyte cells, whereas ET B mRNA was almost exclusively localized on nonmyocyte cells. ET A -and ET B -specific receptor binding was increased on both myocytes and cardiac membranes, showing a positive correlation with left ventricular ejection fraction in ICM (rϭ0.78 and 0.70) but not in DCM patients. The present results show that human ventricular myocytes express all of the components of the ET-1 system, which is selectively upregulated in ICM patients and appears to be functionally important in the maintenance of cardiac function. (Circ Res. 2000;86:377-385.)Key Words: endothelin Ⅲ heart failure Ⅲ myocytes Ⅲ receptors Ⅲ RNA E ndothelin (ET)-1 is a multifunctional peptide that exerts pleiotropic activities, including arterial and venous constriction, direct positive inotropic and chronotropic effects on isolated heart, and growth effects on vascular smooth muscle cells, fibroblasts, and isolated cardiomyocytes. 1 Prepro-ET-1 (ppET-1) mRNA is expressed by both rat and human cardiac myocytes and interstitial cells that synthesize and secrete mature ET-1. [2][3][4] The protease that catalyzes the conversion (ET-converting enzyme, ECE) from the 38-residue inactive intermediate big ET-1 to achieve ET-1 is expressed in the endocardium and myocardium. 5 The differing biological activities of ET-1 appear to be mediated through 2 receptor subtypes (ET A and ET B ), 6 which are both present in the human myocardium and that of other species. 7 Thus, a complete ET-1 system is represented in human myocardium.Cardiac ppET-1 mRNA expression and ET-1 synthesis have been found to be increased in experimental hypertrophy by pressure overload 8 -10 and in experimental models of congestive heart failure (CHF), [11][12][13] thus suggesting that the cardiac ET-1 system may be involved in cardiac diseases.There have been very f...

ACE-inhibition is superior to endothelin A receptor blockade in preventing abnormal capillary supply and fibrosis of the heart in experimental diabetes

“…It also has been shown that ET-1 mRNA receptor binding is increased in the hearts of diabetic rats [5,44], similar to what is found in cardiac disease [13]. In the present long-term study increased ET-1 and ETA receptor expression could also be demonstrated in diabetic rats.…”

“…One explanation proposed by some authors is that damaged cardiomyocytes are unable to synthesise ET-1 in response to Ang II stimulation [13,39,46]. For diabetes this explanation is excluded by our results.…”

“…ET-1 also mediates, at least in part, the chronic effects of Ang II on blood pressure [9,10]. Conversely, ACE-inhibitors (ACE-i) and Ang II receptor type 1 blockers (AT1) diminish ET-1 expression [11,12,13]. In theory these findings would provide a strong rationale for the combination of endothelin receptor blockers (ET A -RB) with ACE-i or AT1 receptor blockers.…”

Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study

“…The A subtype receptor (ET A ) is mainly found in vascular smooth muscle cells as well as myocardium, myometrium and adrenal cortex. 8 8 ET A is encoded by the type A endothelin receptor (EDNRA) gene, which is a strong candidate gene for BP regulation. However, the few previously published candidate gene studies of EDNRA have in general been of small size, and most have typed only one polymorphism in the gene.…”

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

“…On the other hand, a previous study has demonstrated that the status of high big ET-1 level leads to a change of ET-1 receptor expression. 28 Therefore, as the reason for above discrepancy, there is one possibility that exogenous big ET-1 produces an altered ET-1 receptor expression. In the present study, however, the treatment with big ET-1 had no significant influence on the level of both ET A and ET B receptor mRNA expression in the left ventricle.…”