Investigating the sexual dimorphism in isoproterenol-induced cardiac hypertrophy in Sprague Dawley rats.

Abstract

Distinct differences between sexes exist in various cardiovascular diseases. Moreover, there is a significant correlation between the pathogenesis of cardiac hypertrophy (CH) and the metabolites of arachidonic acid (AA) mediated by cytochrome P450 (CYP) enzymes. The potential link between these sex differences, the levels and the activity of CYP enzymes, and their AA-mediated metabolites remains to be elucidated. Male and female Sprague Dawley rats were injected with 1 mg/kg isoproterenol for 7 days to induce CH. Echocardiography was performed before and after the induction of CH. The hypertrophic markers and CYP enzyme levels were analyzed at the gene and protein levels using real-time polymerase chain reaction and Western blot, respectively. Heart microsomal proteins were incubated with AA, and the resulting metabolites were quantified using liquid chromatography-tandem mass spectrometry. Both sexes showed a significant degree of CH, albeit to varying extents, as the echocardiograph, heart weight/tibial length, and left ventricular parameters proved. In addition, the β/α-myosin heavy chain was 2-fold higher in male compared with female rats. Albeit the 20-hydroxyeicosatetraenoic acid (20-HETE) metabolite formation showed no increase in both sexes, the mid-chain HETEs (5- and 15-HETE) were higher in male rats, which paralleled the increase in the gene and protein levels of CYP1B1. The formation rate of the epoxyeicosatrienoic acids was almost unchanged in female-treated rats, while it was significantly decreased in male-treated rats. Our results suggest sexual dimorphism in the isoproterenol-induced CH in rats, specifically on the level of CYP enzymes and their AA-mediated metabolites. SIGNIFICANCE STATEMENT: Sexual dimorphism was observed in rats following isoproterenol-induced cardiac hypertrophy, with males showing a stronger hypertrophic response. This was linked to higher CYP1B1 gene and protein expression in males, along with sex-related differences in many cytochrome P450 enzyme activities and their mediated arachidonic acid metabolites. These findings emphasized the need for targeted, sex-specific therapeutic strategies for the management and treatment of cardiac hypertrophy and other cardiovascular disorders.