The Aldosterone Synthase (CYP11B2) and 11β-Hydroxylase (CYP11B1) Genes Are Not Expressed in the Rat Heart

Abstract

Aldosterone synthase (CYP11B2) and 11beta-hydroxylase (CYP11B1) catalyze the production of aldosterone and corticosterone, respectively, in the rat adrenal cortex. Recently, there has been some debate as to whether these corticosteroids are also produced in the hearts of rodents and humans, possibly contributing to the development of hypertrophy and myocardial fibrosis. To investigate this, we have used our established, highly sensitive real-time quantitative RT-PCR method to measure CYP11B1 and CYP11B2 mRNA levels in adrenal and cardiac tissue from several rat models of cardiovascular pathology. We have also studied isolated adult rat ventricular myocytes treated with angiotensin II and ACTH. Total RNA was isolated from the adrenal and cardiac tissue of 1) male Wistar rats with heart failure induced by coronary artery ligation and sham-operated controls; 2) stroke-prone spontaneously hypertensive rats and Wistar Kyoto rats as controls; 3) cyp1a1Ren-2 transgenic rats and Fischer controls; 4) isolated adult Sprague-Dawley ventricular myocytes incubated with 11-deoxycorticosterone (DOC), DOC plus angiotensin II, or DOC plus ACTH. Adrenal CYP11B2 expression was significantly increased in transgenic rats compared with Fischer controls (1.3 x 10(9)+/- 1.2 x 10(9) vs. 2.1 x 10(7) +/- 7.0 x 10(6) copies/microg RNA; P < 0.05). There were no other significant differences in adrenal CYP11B2 or CYP11B1 expression between the model animals and their respective controls. Cardiac CYP11B1 and CYP11B2 mRNA transcript levels from all in vivo and in vitro groups were never greater than 100 copies per microgram total RNA and therefore too low to be detected reproducibly. This suggests that cardiac corticosteroid production is unlikely to be of any physiological or pathological significance.

Mineralocorticoid Receptor Antagonism Attenuates Cardiac Hypertrophy and Prevents Oxidative Stress in Uremic Rats

“…Similar findings were obtained recently by Chai et al 24 We found no significant differences between the cardiac aldosterone content of sham and NPX rats and very low levels of CYP11B2 expression in the heart. Also, Ye et al 16 did not observe any increase in cardiac CYP11B2 in several rat models of cardiac pathology. Therefore, heart aldosterone synthesis appears not to be implicated in cardiac MR activation of experimental chronic renal failure.…”

Glucocorticoids Activate Cardiac Mineralocorticoid Receptors During Experimental Myocardial Infarction

“…Although cardiac synthesis of aldosterone has had a relatively long and disputed 40 history, the most recent reports from vigorously controlled studies on levels of steroidogenic enzyme mRNA are widely regarded as providing a definitive negative answer to the question of cardiac aldosterone synthesis. 41,42 This is strong evidence that the protective inverse agonist effect of spironolactone is via MRs, for which spironolactone has much higher affinity than for androgen, progesterone, or GRs. In addition to the report already cited, 20 there are cell culture studies 43,44 in which spironolactone alone produced substantial changes, for example, in integrin expression in neonatal cardiomyocytes.…”

Effects of Aldosterone on the Vasculature

“…30 Indeed, in the rat heart, for example, there is little evidence that aldosterone synthase (CYP11B2) and 11(␤)-hydroxylase (CYP11B1) genes are expressed, because there is either extremely low expression of mRNA or protein for steroidogenic enzymes or they are not found at all. 31 Cardiac and vascular MRs have also been demonstrated. 5 Aldosterone induces fibrosis in heart, blood vessels, and kidney, particularly in the presence of high salt.…”