RESUMO
Pharmacological blockade of mineralocorticoid receptors (MR) is known as an efficacious therapy in chronic heart failure. Therapy with steroidal MR antagonists such as spironolactone or eplerenone (EPL) is often limited because of side effects. Recently, a new highly selective and potent, nonsteroidal MR antagonist, finerenone (FIN), has been developed. To investigate the effects of FIN on pressure-induced cardiac hypertrophy, the transverse aortic constriction (TAC) model was used in C57BL/6 mice treated with FIN (10 mg·kg·d), EPL (200 mg·kg·d) or vehicle (VEH). First, we analyzed cardiac gene expression 4 weeks after TAC using a pathway-focused quantitative polymerase chain reaction array. FIN caused a distinct cardiac gene expression profile compared to VEH and EPL, including differential expression of BNP (brain natriuretic peptide) and Tnnt2 (troponin T type 2). FIN treatment led to a significant reduction of TAC-induced left ventricular (LV) wall thickening assessed by echocardiography. In accordance, FIN-treated mice showed a significant lower increase of calculated left ventricular mass compared with VEH- and EPL-treated mice (FIN: 28.4 ± 3.7 mg; EPL: 38.4 ± 4.3 mg; VEH: 39.3 ± 3.1 mg; P < 0.05). These data show beneficial effects of nonsteroidal MR antagonism by FIN on left ventricular mass development in pressure overload associated with a distinct cardiac gene expression profile.
Assuntos
Cardiomegalia/tratamento farmacológico , Cardiomegalia/fisiopatologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Naftiridinas/farmacologia , Espironolactona/análogos & derivados , Animais , Modelos Animais de Doenças , Eplerenona , Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeo Natriurético Encefálico/metabolismo , Espironolactona/farmacologia , Troponina T/metabolismo , Remodelação Ventricular/efeitos dos fármacosRESUMO
In the present study we investigated the influence of sex difference on the development of left ventricular hypertrophy (LVH) during obesity. Male and female C57BL/6J mice were fed for 15 and 25 wk with a high-fat diet (HFD) or low-fat control diet (LFD). Analysis of body composition, monitoring of body weight (BW), and echocardiographic analysis were performed, as well as analysis of expression of different adipocytokines in epicardial adipose tissue. The increment in left ventricular mass (LVM) after HFD (25 wk) was significantly stronger in male mice compared with female mice [LVM: male, 116.9 ± 2.9 (LFD) vs. 142.2 ± 9.3 mg (HFD); female, 84.3 ± 3.3 (LFD) vs. 93.9 ± 1.7 mg (HFD), Psex < 0.01]. In parallel, males developed a higher BW and fat mass after 25 wk HFD than female mice [BW: male, 33 ± 0.9 (LFD) vs. 53 ± 0.8 g (HFD); fat mass: male, 8.8 ± 0.9 (LFD) vs. 22.8 ± 0.7 g (HFD); BW: female, 22.5 ± 0.4 (LFD) vs. 33.7 ± 1.3 g (HFD); fat mass: female, 4.0 ± 0.2 (LFD) vs. 13.2 ± 1.2 g (HFD)] (P < 0.01 for BW+ fat mass female vs. male). The mRNA expression of adipocytokines in epicardial fat after 25 wk of diet showed higher levels of adiponectin (2.8-fold), leptin (4.2-fold), and vaspin (11.9-fold) in male mice compared with female mice (P < 0.05). To identify new adipose-derived molecular mediators of LVH, we further elucidated the cardiac impact of vaspin. Murine primary cardiac fibroblast proliferation was significantly induced by vaspin (1.8-fold, vaspin 1 µg/l, P < 0.05 vs. control) compared with 1.9-fold induction by angiotensin II (10 µM). The present study demonstrates a sex-dependent regulation of diet-induced LVH associated with sexual dimorphic expression of adipocytokines in epicardial adipose tissue.