Vascular Angiotensin-Converting Enzyme Expression Regulates Local Angiotensin II

Abstract

We tested the hypothesis that changes in angiotensin-converting enzyme (ACE) gene expression can regulate the rate of local vascular angiotensin II (Ang II) production. We perfused isolated rat hindlimbs with an artificial medium and infused renin and Ang I via the perfusate. Ang I and II were measured by radioimmunoassay. We then increased ACE gene expression and ACE levels in the rat aorta by producing two-kidney, one clip (2K1C) hypertension for 4 weeks. Gene expression was measured by RNAse protection assay, and ACE activity in the vessel wall was measured by the Cushman-Cheung assay. Angiotensin I infusion at 1, 10, 100, and 1000 pmol/mL led to 371 +/- 14 (+/-SEM), 3611 +/- 202, 44,828 +/- 1425, and 431,503 +/- 16,439 fmol/mL Ang II released, respectively, from the hindlimbs (r = .98, P < .001). Thus, the conversion rate did not change across four orders of magnitude, and the system was not saturable under these conditions. In 2K1C hindlimbs, Ang I infusion (0.5 pmol/mL) resulted in increased Ang II generation (157 +/- 16 versus 123 +/- 23 fmol/mL, P = .014 at minute 10) compared with controls. ACE gene expression and ACE activity were increased in 2K1C hindlimbs compared with controls (36 +/- 4 versus 17 +/- 1 mU/mg protein, P < .001). Ang II degradation in the two groups did not differ. To investigate the conversion of locally generated Ang I, we infused porcine renin (0.5 milliunits per mL) into 2K1C and control hindlimbs. Despite markedly higher Ang I release in sham-operated than in 2K1C rats (71 +/- 8 versus 37 +/- 6 pmol/mL, P = .008 at minute 12), Ang II was only moderately increased (36 +/- 3 versus 25 +/- 6 pmol/mL, P = .12 at minute 12). This difference between 2K1C rats and controls reflected a higher rate of conversion in 2K1C rats. Thus, Ang I conversion in the rat hindlimb is linear over a wide range of substrate concentrations and occurs at a fixed relationship. Nevertheless, increased ACE gene expression and ACE activity in the vessel wall lead to an increase in the conversion of Ang I to Ang II. We conclude that local ACE gene expression and ACE activity can influence the local rate of Ang II production.

Polymorphisms of the renin-angiotensin system in patients with multifocal renal arterial fibromuscular dysplasia

“…29 Muller et al, 51 using perfused isolated rat hindquarters in rats with and without two-kidney one clip (2K1C) hypertension, showed that increased ACE gene expression and ACE levels led to an increase in conversion of Ang I to Ang II. Therefore, the ACE I allele is probably associated with lower local concentrations of Ang II.…”

Antihypertensive treatment modulates the association between the D/I ACE gene polymorphism and left ventricular hypertrophy: a meta-analysis

“…First, there is mounting evidence that increased ACE gene expression and ACE activity may stimulate the local rate of angiotensin II production [46][47][48][49] and, in turn, may promote cardiac growth. Second, the D variant of the ACE gene may act only under specific conditions, when physiologic or pathophysiologic processes stimulate left ventricular enlargement.…”

Micropuncture determination of nephron function in mice without tissue angiotensin-converting enzyme

“…Nevertheless, it has become clear that in addition to the so-called systemic renin-angiotensin system, production of angiotensin II can also occur by enzymesubstrate interactions within certain tissues (11). The most consistent of these tissue renin-angiotensin systems are found in the brain and in the kidney, but such local angiotensin generation appears to be a characteristic of many other tissues as well (9,12,22).…”