Differential Regulation of Cardiac Angiotensin Converting Enzyme Binding Sites and AT ₁ Receptor Density in the Failing Human Heart

Abstract

Background-The regulation and interaction of ACE and the angiotensin II (Ang II) type I (AT 1 ) receptor in the failing human heart are not understood.

Cardiac Angiotensin II Formation in the Clinical Course of Heart Failure and Its Relationship With Left Ventricular Function

“…2 However, few studies have investigated the cardiac reninangiotensin system (RAS) in human hypertrophy and heart failure (HF), as opposed to the large number of experimental studies performed in cell culture systems and experimental models (for studies, see Wollert and Drexler 3 ). In human explanted failing hearts, levels of angiotensin-converting enzyme (ACE) mRNA, 4 ACE activity, and ACE binding sites 5 have been found to be increased as compared with control hearts. Levels of prorenin, renin, and ACE measured with enzyme kinetics are higher in failing than in control hearts.…”

“…Several groups have investigated the density of Ang II receptor subtypes in human failing hearts and have found a reduction in AT 1 , 5,9 -11 either without changes in AT 2 9,10 or with an increase in them. 5,11 However, these studies were only performed on myocardial homogenates, and no information is available on the regulation of Ang II receptor subtypes on myocytes and nonmyocyte cells. A last but no less important question is the functional significance of cardiac Ang II formation in myocardial hypertrophy and HF.…”

Translational Success Stories: Angiotensin Receptor 1 Antagonists in Heart Failure

“…60 -62 Studies over the past 20 years further supported local synthesis of most of the RAS components, particularly ACE and Ang II, that were also related to the severity of heart failure in the dog with volume overload, 63 rats with pressure overload, 64 and in patients with heart failure. 65 The question whether renin was synthesized locally remained controversial; 66 however, over the past 10 years there were major advances in knowledge of renin and prorenin and the prorenin/renin receptor.…”

Inhibiting Tissue Angiotensin-Converting Enzyme

“…ACE protein expression is increased in the failing human heart, and this increase may occur as the result of ACE gene expression in both endothelial cells and cardiac myocytes. 16 Thus, the pertinent question may not be simply whether one is effectively inhibiting endothelial ACE but also whether effective inhibition of cardiac myocyte ACE has been achieved. Similarly, the inducible form of NOS (iNOS) is increased in cardiac myocytes from failing human hearts relative to ecNOS.…”