Sex-related survival differences in murine cardiomyopathy are associated with differences in TNF-receptor expression

Abstract

IntroductionEpidemiologic studies have observed important differences in survival between men and women with heart failure (1-5). For example, the population-based Framingham Heart Study found that after the onset of symptomatic heart failure, the prognosis of women was significantly better than men (3,4). Similar observations were reported in patients with advanced heart failure, and these sex-related differences could not be attributed to a high incidence of coronary disease in men (1, 2). Furthermore, hormone-replacement therapy appeared to effect improved survival in postmenopausal women with nonischemic heart failure (6).Sex-related differences in the physiologic response to stress have also been identified in spontaneously hypertensive rats (7), transgenic mice overexpressing the cardiac Na + /Ca 2+ exchanger (8), and rats with pressure overload-induced hypertrophy (9). However, studies in these animal models of heart failure have not assessed sexrelated survival nor have they elucidated underlying mechanisms that could account for these differences.Recently, we developed transgenic mice (TNF1.6) with cardiac-specific overexpression of TNF-α and have characterized their progression to congestive heart failure (10, 11). These transgenic mice developed ventricular hypertrophy, cardiac dilatation, interstitial infiltrates and fibrosis, attenuation of adrenergic responsiveness, and re-expression of atrial natriuretic factor in the ventricle. These mice had a 6-month mortality of nearly 25%. Furthermore, the mice that died spontaneously demonstrated exceptional dilatation of the heart, organized atrial thrombus, and massive pleural effusion, suggesting that they died of congestive heart failure (10). These characterizations have been confirmed by a separate group studying a similar transgenic model (12,13). In this study we report the presence of sex-related differences in survival of TNF1.6 mice and have begun to elucidate cellular pathways that might be of etiologic importance in affecting sexrelated differences. Methods TNF-α transgenic mice.Studies used previously characterized transgenic mice (TNF1.6) (10). For RNA and protein analysis, animals were sacrificed, and excised ventricle or liver tissues were snap-frozen in liquid nitrogen. Blood samples were collected, and peripheral white blood cells were isolated by lysing erythrocytes with 1.7% NH 4 Cl. The mice were handled according to protocols approved by the Institutional Animal Care and Use Committee, University of Pittsburgh.Experimental design. Survival analysis was used to assess differences between male and female transgenic mice. Echocardiography was performed to compare the cardiac structure and function between the sexes in vivo. To assess whether phenotypic differences arose from differ- Epidemiological evidence suggests that the prognosis of heart failure in women is better than in men. In our murine model of dilated cardiomyopathy arising from cardiac-specific overexpression of TNF-α, the 6-month survival rate was significantly better in fem...

Ablation of cyclase-associated protein 2 (CAP2) leads to cardiomyopathy

“…In our studies, we observed that DCM developed in both female and male mutant mice, but mortality was more pronounced in male mice than females. This is in accordance with previous studies showing that female sex protects against the severity and frequency of DCM [36,37]. Many studies in a number of mouse strains revealed multiple differences between male and female animals.…”

“…Many studies in a number of mouse strains revealed multiple differences between male and female animals. Transgenic overexpression of phospholamban, TNF-a, b2AR, NCX showed a gender-related discrepancy in the cardiac phenotype in which the more severe phenotype was observed in males [38][39][40][41]. Similarly, gene disruption of FKBP12.6, phospholamban, and ERa revealed a cardiac phenotype with male preponderance [42][43][44].…”

TNF Receptor 1/2 Predict Heart Failure Risk in Type 2 Diabetes Mellitus Patients

“…TNFR1 is expressed in nearly all cell types (except erythrocytes), while TNFR2 is found primarily in cells of the immune system and myocardial cells. 28,29) Previous research suggests TNFR1/2 signaling is complex; TNFR1 could aggravate while TNFR2 ameliorates chamber remodeling and hypertrophy due to their different effects on NF-kB, JNK, inflammatory activation, and apoptosis. 30) In our study, we compared inflammatory expression in different groups.…”

The Effects of Biological Sex and Diet on the Development of Heart Failure

“…Male death rate reaches Ϸ50% by 20 weeks of age, compared with 4% in females. 89 The potential mechanism of this sex difference may be related to elevated circulating levels of TNF-␣ in postmenopausal women. 90 In a recent study, estrogen replacement in ovariectomized rats decreases circulating TNF-␣ after ischemia/reperfusion injury, with a concomitant decrease in TNF receptor 2 and increase in TNF receptor 1.…”