Pathological growth of cardiomyocytes (hypertrophy) is a major determinant for the development of heart failure, one of the leading medical causes of mortality worldwide. Here we show that the microRNA (miRNA)-212/132 family regulates cardiac hypertrophy and autophagy in cardiomyocytes. Hypertrophic stimuli upregulate cardiomyocyte expression of miR-212 and miR-132, which are both necessary and sufficient to drive the hypertrophic growth of cardiomyocytes. MiR-212/132 null mice are protected from pressure-overload-induced heart failure, whereas cardiomyocyte-specific overexpression of the miR-212/132 family leads to pathological cardiac hypertrophy, heart failure and death in mice. Both miR-212 and miR-132 directly target the anti-hypertrophic and pro-autophagic FoxO3 transcription factor and overexpression of these miRNAs leads to hyperactivation of pro-hypertrophic calcineurin/NFAT signalling and an impaired autophagic response upon starvation. Pharmacological inhibition of miR-132 by antagomir injection rescues cardiac hypertrophy and heart failure in mice, offering a possible therapeutic approach for cardiac failure.

In addition to their role in controlling water and salt homeostasis, recent work suggests that aldosterone and mineralocorticoid receptors (MR) may be involved in adipocyte biology. This is of particular relevance given the role of MR as a high‐affinity receptor for both mineralocorticoids and glucocorticoids. We have thus examined the effect of aldosterone and MR on white adipose cell differentiation. When cells are cultured in a steroid‐free medium, aldosterone promotes acquisition of the adipose phenotype of 3T3‐L1 and 3T3‐F442A cells in a time‐, dose‐, and MR‐dependent manner. In contrast, late and long‐term exposure to dexamethasone inhibits adipocyte terminal maturation. The aldosterone effect on adipose maturation was accompanied by induction of PPARγ mRNA expression, which was blocked by the MR antagonist spironolactone. Under permissive culture conditions, specific MR down‐regulation by siRNAs markedly inhibited 3T3‐L1 differentiation by interfering with the transcriptional control of adipogenesis, an effect not mimicked by specific inactivation of the glucocorticoid receptor. These results demonstrate that MR represents an important proadipogenic transcription factor that may mediate both aldosterone and glucocorticoid effects on adipose tissue development. MR thus may be of pathophysiological relevance to the development of obesity and the metabolic syndrome.–Caprio, M., Fève, B., Claës, A., Viengchareun, S., Lombès, M., Zennaro, M‐C. Pivotal role of the mineralocorticoid receptor in corticosteroid‐induced adipogenesis. FASEB J. 21, 2185–2194 (2007)

In clinical trials, aldosterone antagonists decrease cardiovascular mortality and ischemia by unknown mechanisms. The steroid hormone aldosterone acts by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor. In humans, aldosterone causes MR-dependent endothelial cell (EC) dysfunction and in animal models, aldosterone increases vascular macrophage infiltration and atherosclerosis. MR antagonists inhibit these effects without changing blood pressure, suggesting a direct role for vascular MR in EC function and atherosclerosis. Whether human vascular ECs express functional MR is not known. Here, we show that human coronary artery and aortic ECs express MR mRNA and protein and that EC MR mediates aldosterone-dependent gene transcription. Human ECs also express the enzyme 11-β-hydroxysteroid dehydrogenase-2 (11βHSD2), and inhibition of 11βHSD2 in aortic ECs enhances gene transactivation by cortisol, supporting that EC 11βHSD2 is functional. Furthermore, aldosterone stimulates transcription of the proatherogenic leukocyte–EC adhesion molecule intercellular adhesion molecule (ICAM)1 gene and protein expression on human coronary artery ECs, an effect inhibited by the MR antagonist spironolactone and by MR knock down with small interfering RNA. Cell adhesion assays demonstrate that aldosterone promotes leukocyte–EC adhesion, an effect that is inhibited by spironolactone and ICAM1 blocking antibody, supporting that aldosterone induction of EC ICAM1 surface expression via MR mediates leukocyte–EC adhesion. These data show that aldosterone activates endogenous EC MR and proatherogenic gene expression in clinically important human ECs. These studies describe a novel mechanism by which aldosterone may influence ischemic cardiovascular events and support a new explanation for the decrease in ischemic events in patients treated with aldosterone antagonists.

Leptin circulates in plasma at concentrations that parallel the amount of fat reserves. In obese males, androgen levels decline in proportion to the degree of obesity. Recently, we have shown that in rodent Leydig cells leptin inhibits hCG-stimulated testosterone (T) production via a functional leptin receptor isoform; others have found that leptin inhibits basal and hCG-induced T secretion by testis from adult rats. In this study, we further investigated the relationship linking leptin and androgens in men. Basal and hCG-stimulated leptin and sex hormone levels were studied in a large group of men ranging from normal weight to very obese (body mass index, 21.8–55.7). Initial cross-sectional studies showed that circulating leptin and fat mass (FM) were inversely related with total and free T (r = −0.51 and r = −0.38, P < 0.01 and P < 0.05, respectively). Multiple regression analysis indicated that the correlation between leptin or FM and T was not lost after controlling for SHBG and/or LH and/or estradiol (E₂) levels and that leptin was the best hormonal predictor of the lower androgen levels in obesity. Dynamic studies showed that in obese men the area under the curve of T and free T to LH/hCG stimulation (5000 IU im) was 30–40% lower than in controls and inversely correlated with leptin levels (r = −0.45 and r = −0.40, P < 0.01 and P < 0.05, respectively). Also, LH/hCG-stimulation caused higher increases in 17-OH-progesterone to T ratio in obese men than in controls, whereas no differences were observed between groups either in stimulated E₂ levels or in the E₂/T ratio. In all subjects, the percentage increases from baseline in the 17-OH-progesterone to T ratio were directly correlated with leptin levels or FM (r = 0.40 and r = 0.45, P < 0.01), but not with E₂ or other hormonal variables. In conclusion, our studies, together with previous in vitro findings, indicate that excess of circulating leptin may be an important contributor to the development of reduced androgens in male obesity.