Mineralocorticoid receptor blockade prevents Western diet-induced diastolic dysfunction in female mice

作者：Bostick Brian; Habibi Javad; DeMarco Vincent G; Jia Guanghong; Domeier Timothy L; Lambert Michelle D; Aroor Annayya R; Nistala Ravi; Bender Shawn B; Garro Mona; Hayden Melvin R; Ma Lixin; Manrique Camila; Sowers James R^*

来源：American Journal of Physiology - Heart and Circulatory Physiology, 2015, 308(9): H1126-H1135.

DOI：10.1152/ajpheart.00898.2014

• mineralocorticoid antagonism
• low-dose spironolactone
• aldosterone
• high-fat diet
• high-fructose diet
• oxidative stress
• inflammation
• cardiac hypertrophy
• myocardial compliance

Overnutrition/obesity predisposes individuals, particularly women, to diastolic dysDD), an independent predictor of future cardiovascular disease. We examined whether low-dose spironolactone (Sp) prevents DD associated with consumption of a Western Diet (WD) high in fat, fructose, and sucrose. Female C57BL6J mice were fed a WD with or without Sp (1 mg.kg(-1).day(-1)). After 4 mo on the WD, mice exhibited increased body weight and visceral fat, but similar blood pressures, compared with control diet-fed mice. Sp prevented the development of WD-induced DD, as indicated by decreased isovolumic relaxation time and an improvement in myocardial performance (<Tei index) and septal annular velocity (<E' -to-A' ratio), as assessed by echocardiography, as well as decreased diastolic relaxation time/increased diastolic initial filling rate, as assessed by MRI. The relationship between passive sarcomere length of cardiac myocytes and ventricular pressure was monitored using di-8-ANEPPS staining of the t-tubule network in hearts ex vivo. Sp administration led to longer sarcomere lengths at each pressure indicative of improved ventricular compliance in WD-fed mice. Sp also prevented left ventricular hypertrophy, interstitial fibrosis, and oxidative stress. Sp prevented the WD-induced increased expression of myocardial proinflammatory M1 macrophage markers monocyte chemoattractant protein-1 and CD11c and increased the expression of the anti-inflammatory M2 macrophage marker CD206. These findings demonstrate that WD-induced DD is associated with increased oxidant stress, fibrosis, and immune dysregulation. Mineralocorticoid receptor antagonism enhanced M2 macrophage polarization and ameliorated oxidant stress and fibrosis. This work supports a novel blood pressure-independent effect of MR antagonism as a strategy to prevent diet-induced DD in women.

• 出版日期2015-5-1