Cardiovascular Dysfunction in Hypercholesterolemia Associated With Enhanced Formation of ATI-Receptor and of Eicosanoids

Abstract

Background: In hypercholesterolemia with or without atherosclerosis cardiovascular dys function and altered signalling of angiotensin (Ang II), nitric oxide (NO), or prostanoids are intimately related to enhanced oxidant stress and concomitant changes in gene expression. We analyzed cardiac angiotensin receptor (AT1) expression and metabolism of Ang II, eicosanoids, and NO in hypercholesterolemic animals.

Methods: Guinea pigs were fed a 1% cholesterol diet for 8 weeks (Chol). Hemodynamics were analyzed in Langendorff hearts. Spectrophotometric determination of plasma lipids and radioimmunological detection of eicosanoids/cyclic guanosine monophosphate (cGMP). Ac tivities of NO synthase III (NOS-III) or angiotensin converting enzyme (ACE) were deter mined by enzymatic assays. AT1 receptor density was assessed by radioligand binding assay. NOS-III mRNAs were quantitated by reverse transcription polymerase chain reaction.

Results: Hypercholesterolemia was associated with fatty degeneration of the liver and pro found myocardial and coronary (e.g., endothelial) dysfunction. In Chol Langendorff hearts we observed significant increases in coronary flow (26.0 ± 1.0 vs. 17.5 ± 0.5 mL/min/g tissue) but diminished coronary responses to bradykinin (Bk, 250 ng bolus) or adenosine (Ado, 250 μg bolus) (ΔCPP_Bk/Ado: 5 ± 0.5 vs. 7.2 ± 1/0.9 ± 0. 1 vs. 1.9 ± 0.3 cm² (area under the curve)). AT1 receptor expression was significantly increased in Chol hearts (72 ± 6.8 vs. 45 ± 5.6 fmol/mg protein), whereas marked suppression of cardiac activities of ACE (1.96 ± 0.34 vs. 4.90 ± 0.20 nmol/min/mg tissue) and of the entire cardiac nitric oxide-cGMP axis (e.g., NOS-III activity: 1.9 ± 0.4 vs. 3.1 ± 0.1 pmol/min/mg tissue; NOS-III mRNA: 0.82 ± 0.16 vs. 1.20 ± 0.12 arbitrary units; cGMP release: 0.41 ± 0.02 vs. 0.54 ± 0.04 pmol/min/g tissue) were shown in Chol. Finally, cardiac release of eicosanoids prostacyclin (PGI₂) and throm boxane (TxA₂) were significantly enhanced (0.48 ± 0.05 vs. 0.38 ± 0.05 and 0.60 ± 0.10 vs. 0.24 ± 0. 10 ng/min/g tissue, respectively). Enhanced cardiac PGI₂ release and suppression of cGMP synthesis in Chol were even more pronounced on stimulation with Bk (38.2 ± 3.0 vs. 28.2 ± 2.0 ng/min/g tissue and 1.9 ± 0.3 vs. 3.0 ± 0.3 pmol/min/g tissue, respectively).

Conclusions: Altered angiotensin-mediated signal transduction probably related to aug mented eicosanoid formation does not compensate for the limited endogenous NO production and for cardiovascular dysfunction in hypercholesterolemic guinea pigs. In this context, changes in redox-sensitive regulation of gene expression (ATI receptor, NOS-III—caused by enhanced oxidant stress—coutd play a pivotal role.