Abstract 631: Cardiomyocyte-specific Cyp4a12a Overexpression Aggravates Maladaptive Cardiac Hypertrophy

Abstract

Alterations in cytochrome P450 (CYP)-dependent formation of 20-hydroxyeicosatetraenoic acid (20-HETE) are associated with hypertension and end-organ damage. The cause-and-effect relationships are only partially understood and difficult to dissect due to the multiple and partially opposing roles of 20-HETE in different tissues. We established a Cre/loxP-system for tissue-specific overexpression of Cyp4a12a, a murine 20-HETE producing isoform. We used this system to test the hypothesis that enhanced formation of 20-HETE plays a detrimental role in cardiac hypertrophy. Floxed Cyp4a12a mice were crossed with alpha-MHC-Cre mice to generate animals with cardiomyocyte-specific Cyp4a12a overexpression (CYP) and wildtype littermates (WT). RT-PCR and immunohistochemistry confirmed Cyp4a12a overexpression in CYP compared to WT hearts. The animals (n=10-12 per group) were subjected to transverse aortic constriction (TAC). Eight weeks after TAC, the left ventricular mass-to-tibia length ratio (mg/mm) increased to 14.6±2.3 in male WT and to 12.6±2.3 in male CYP mice. Hypertrophy was lower in WT females (11.2±1.4) but not in CYP females (12.3±2.1), compared to their male counterparts. ANP and βMHC expression levels were higher in CYP than WT mice (2.6- and 2.2-fold in males, and 1.9- and 1.8-fold in females). The ejection fraction (%) was more severely impaired in the CYP than WT groups (male WT: 22.3±4.7 vs. CYP: 9.5±3.4; female WT: 21.8±11.7 vs. CYP: 15.5±4.8). Cyp4a12a overexpression also worsened TAC-induced end-diastolic posterior wall thinning (male WT: 1.05±0.17 vs. CYP: 0.80±0.12; female WT: 0.93±0.12 vs. CYP: 0.85±0.11mm), and dilation (male WT: 5.21±0.53 vs. TG: 5.83±0.53; female WT: 4.82±0.56 vs. CYP: 5.39±0.43mm). Moreover, the interventricular septal thickness was clearly reduced in male CYP compared to WT hearts after TAC. The lung weight was markedly higher in male CYP than WT mice (WT: 201.4±90.9 vs. CYP: 485.3±50.7 mg), but not different in female groups. These results demonstrate that cardiomyocyte-specific overexpression of Cyp4a12a/20-HETE aggravates pressure overload-induced maladaptive hypertrophy and promotes the development of dilated cardiomyopathy. The effects were more pronounced in males compared to females.