Oxidative stress is implicated in menopause-associated hypertension and cardiovascular disease. The role of antioxidants in this process is unclear. We questioned whether down-regulation of thioredoxin (Trx) is associated with oxidative stress and development of hypertension and target-organ damage (cardiac hypertrophy) in a menopause model. Trx is an endogenous antioxidant that also interacts with signaling molecules, such as apoptosis-signal-regulated kinase 1 (ASK-1), independently of its antioxidant function. Aged female wild type (WT) and follitropin receptor knockout (FORKO) mice (20-24weeks), with hormonal imbalances, were studied. Mice were infused with Ang II (400ng/kg/min, 14 days). Systolic blood pressure was increased by Ang II in WT (166±8mmHg vs. 121±5mmHg) and FORKO mice (176±7mmHg vs. 115±5mmHg, P<0.0001, n=9/group). In Ang II-infused FORKO mice, cardiac mass was increased by 42% (P<0.001). This was associated with increased collagen content and augmented ERK 1/2 phosphorylation (2-fold). Cardiac Trx expression and activity were decreased by Ang II in FORKO but not in WT (P<0.01). ASK-1 expression, cleaved caspase III content and Bax/bcl2 content were increased in Ang II-infused FORKO (P<0.05). Ang II had no effect on cardiac NAD(P)H oxidase activity nor on •O₂^- levels in WT or FORKO. Cardiac AT1R expression was similar in FORKO and WT. These findings indicate that in female FORKO , Ang II-induced cardiac hypertrophy and fibrosis are associated with Trx downregulation and upregulation of ASK-1/caspase signaling. Our data suggest that in a model of menopause, protective actions of Trx may be blunted, which could contribute to cardiac remodeling independently of oxidative stress and hypertension.