PGC-1 upregulation via estrogen receptors: a common mechanism of salutary effects of estrogen and flutamide on heart function after trauma-hemorrhage

Abstract

Flutamide, an androgen receptor antagonist, is thought to improve cardiovascular function by blocking the androgen receptor after trauma-hemorrhage (T-H). Although 17beta-estradiol (E2) and flutamide improve cardiac function after T-H, whether E2 and flutamide produce their salutary effect via the same or a different mechanism is unknown. We hypothesized that E2 and flutamide mediate their effects via estrogen receptor (ER)-mediated upregulation of peroxisome proliferator-activated receptor coactivator 1 (PGC-1). PGC-1, a key regulator of cardiac mitochondrial function, induces mitochondrial genes by activating transcription factors such as nuclear respiratory factor 2 (NRF-2), which regulates mitochondrial proteins [i.e., mitochondrial transcription factor A (Tfam), cytochrome-c oxidase subunit IV, and beta-ATP synthase]. Adult male rats underwent T-H [5-cm midline incision and hemorrhage (blood pressure = 40 mmHg for approximately 90 min)] and resuscitation. At the onset of resuscitation, rats received vehicle, flutamide (25 mg/kg), or E2 (50 microg/kg). Another group received the ER antagonist ICI-182780 (3 mg/kg) with or without flutamide. Flutamide or E2 administration after T-H restored depressed cardiac function. Moreover, E2 and flutamide normalized expression of cardiac PGC-1, NRF-2, Tfam, cytochrome-c oxidase subunit IV, and the mitochondrial DNA-encoded gene cytochrome-c oxidase subunit I and beta-ATP synthase, mitochondrial ATP, and cytochrome-c oxidase activity. However, if the ER antagonist ICI-182780 was administered with flutamide, flutamide-mediated PGC-1 upregulation was totally abolished. These results indicate that E2 and flutamide upregulate PGC-1 via the ER. Thus PGC-1 upregulation appears to be the common mechanism by which E2 and flutamide mediate their salutary effects on cardiac function after T-H.

Transverse aortic constriction leads to accelerated heart failure in mice lacking PPAR-γ coactivator 1α

“…As mentioned above, the expression of PGC-1␣ and many of its target genes is repressed in various rodent models of cardiac failure (28)(29)(30)(31)(32)(33)(34)(35)(36). Consistent with these findings, PGC-1␣ was repressed by Ϸ30-40% in WT mice subjected to TAC, compared with WT controls (Fig.…”

“…This finding suggests that a threshold of mitochondrial activity might be required to cope with chronic hemodynamic load, and that the combination of PGC-1␣ repression and aortic banding hastens the falling below that threshold. Repression of PGC-1␣ and genes regulated by PGC-1␣ is also observed in other models of heart failure, even in cases where mitochondrial defects or pressure overload are not the primary etiology of cardiac dysfunction (28)(29)(30)(31)(32)(33)(34)(35)(36). Hence, the data suggest that, even in these cases, repression of PGC-1␣ may be causally involved in the development of heart failure.…”

“…A growing literature indicates that PGC-1␣ expression is altered in experimental models of heart disease (28)(29)(30)(31)(32)(33)(34)(35)(36). For example, PGC-1␣ and mitochondrial genes that are regulated by PGC-1␣ are repressed in rodent models of cardiac hypertrophy (30,31,37).…”

Estrogen-provided cardiac protection following burn trauma is mediated through a reduction in mitochondria-derived DAMPs

“…Similar estrogen protection in brain mitochondria was observed in the models of Alzheimer's disease (66) and aging (40). The proposed mechanisms of estradiol-mediated mitochondrial protection involve estrogen receptors (ERs) (31,72), upregulation of the gene expressions of mitochondrial functional proteins (34,35), and/or the antioxidant feature of estradiol itself (21). Although the exact pathways of how estradiol protects functional mitochondria and regulates the production of mitochondrial DAMPs in the heart during burn still remains to be illustrated, our present data suggest a possible mechanism that involves the upregulation of mitochondrial antioxidant enzymes.…”

“…Our results are consistent with previous reports of estrogen-mediated protection of mitochondrial function in other disease models. For example, estrogen was able to inhibit the downregulation of mitochondrial metabolism in heart, liver, and kidney in response to trauma-hemorrhage injury (34,35,47). Similar estrogen protection in brain mitochondria was observed in the models of Alzheimer's disease (66) and aging (40).…”