1 Adrenoreceptor agonists induce a hypertrophic phenotype in vitro and in vivo. To investigate the molecular remodeling in chronic cardiac hypertrophy we infused adult male mice with vehicle, isoproterenol, phenylephrine or both agonists for 3, 7 or 14 days. 2 All drugs increased cardiac mass. After minipump removal cardiac mass regressed to control levels within 7 days after PE and ISO treatment whereas ISO+PE treated hearts were incompletely regressed. 3 ANF and b-MHC, but not a-MHC, expression were increased by agonists at all time points. GATA-4, Nkx-2.5, Egr-1, c-jun and c-fos expression were increased after 3, 7 and 14 days of treatment. Expression was greatest after ISO+PE44ISO4PE4vehicle infusion suggesting a synergistic eect of adrenoreceptor stimulation and indicating a greater eect of b-than a-adrenergic action in vivo. 4 After PE or ISO drug withdrawal the HW/BW was normal and Egr-1, c-jun, c-fos and GATA-4, but not Nkx2.5, expression dropped to control levels. HW/BW regression was incomplete after ISO+PE and elevated levels of Egr-1, c-jun and Nkx2.5 expression remained. 5 A hydralazine-mediated reduction in blood pressure had no eect on the agonist-induced cardiac hypertrophy or gene expression. 6 In conclusion, we found that continued agonist stimulation, and not blood pressure, is responsible for the maintained increase in gene expression. Further, we found the decrease in gene expression in the regression after drug withdrawal was gene speci®c.

Bisphenol A (BPA) is an estrogenizing endocrine disruptor compound of concern. Our objective was to test whether lifelong BPA would impact cardiac structure/function, calcium homeostasis protein expression, and the DNA methylation of cardiac genes. We delivered 0.5 and 5.0 µg/kg/day BPA lifelong from gestation day 11 or 200 µg/kg/day from gestation day 11 to postnatal day 21 via the drinking water to C57bl/6n mice. BPA 5.0 males and females had increased body weight, body mass index, body surface area, and adiposity. Echocardiography identified concentric remodeling in all BPA-treated males. Systolic and diastolic cardiac functions were essentially similar, but lifelong BPA enhanced male and reduced female sex-specific differences in velocity of circumferential shortening and ascending aorta velocity time integral. Diastolic blood pressure was increased in all BPA females. The calcium homeostasis proteins sarcoendoplasmic reticulum ATPase 2a (SERCA2a), sodium calcium exchanger-1, phospholamban (PLB), phospho-PLB, and calsequestrin 2 are important for contraction and relaxation. Changes in their expression suggest increased calcium mobility in males and reduced calcium mobility in females supporting the cardiac function changes. DNA methyltransferase 3a expression was increased in all BPA males and BPA 0.5 females and reduced in BPA 200 females. Global DNA methylation was increased in BPA 0.5 males and reduced in BPA 0.5 females. BPA induced sex-specific altered DNA methylation in specific CpG pairs in the calsequestrin 2 CpG island. These results suggest that continual exposure to BPA impacts cardiac structure/function, protein expression, and epigenetic DNA methylation marks in males and females.

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