Abstract-Mineralocorticoid receptor (MR) activation may be deleterious to the cardiovascular system, and MR antagonists improve morbidity and mortality of patients with heart failure. However, mineralocorticoid signaling in the heart remains largely unknown. Using a pan-genomic transcriptomic analysis, we identified neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2) as a strongly induced gene in the heart of mice with conditional and targeted MR overexpression in cardiomyocytes (whereas induction was low in glucocorticoid receptor-overexpressing mice). NGAL mRNA levels were enhanced after hormonal stimulation by the MR ligand aldosterone in cultured cardiac cells and in the heart of wild-type mice. Mineralocorticoid pathological challenge induced by nephrectomy/aldosterone/salt treatment upregulated NGAL expression in the heart and aorta and its plasma levels. We show evidence for MR binding to an NGAL promoter, providing a mechanism for NGAL regulation. We propose that NGAL may be a marker of mineralocorticoiddependent injury in the cardiovascular system in mice. (Aldo) is a main regulator of renal sodium reabsorption, with an overall effect on volemia and blood pressure. Aldo binds to the mineralocorticoid receptor (MR), a transcription factor of the nuclear receptor family present in the kidney.1 Extrarenal pathophysiological effects of this hormone have been characterized, extending its actions to the CV system, the brain, the adipose tissue, the skin, and the eye.2-5 Inappropriate MR activation has been shown to promote cardiac fibrosis in experimental models 6,7 The Randomized Aldactone Evaluation Study, 8 Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, 9 and Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure 10 clinical trials have demonstrated that the addition of the MR antagonists spironolactone or eplerenone to standard care markedly reduced the overall and CV mortality in patients with left ventricular systolic dysfunction and mild or severe symptoms of chronic heart failure (HF) or with HF signs after acute myocardial infarction.The molecular mechanisms of Aldo and MR activation in the CV system are not yet fully established. A better understanding of these mechanisms may unveil novel biotargets for pharmacological modulation of the signaling cascades induced by mineralocorticoids in CV diseases.In this study we identified neutrophil gelatinase-associated lipocalin (NGAL) in a pan-genomic transcriptomic analysis performed on hearts of transgenic mice that overexpress the MR in cardiomyocytes. NGAL (lipocalin 2 or 24p3) is a 25-kDa glycoprotein belonging to the lipocalin superfamily.11,12 The cell-specific roles of NGAL remain elusive, but enhanced NGAL in tissues, plasma, or urine has been reported in several pathological states, such as kidney failure 13 and obesity, 14,15 and many other situations. Increased systemic and myocardial expressions of NGAL have been observed in clinical and experimental HF. 16,17 Hormona...

Background: Many patients with heart failure with preserved ejection fraction (HFpEF) are women. Exploring mechanisms underlying the sex differences may improve our understanding of the pathophysiology of HFpEF. Studies focusing on sex differences in circulating proteins in HFpEF patients are scarce. Methods: A total of 415 proteins were analyzed in 392 HFpEF patients included in The Metabolic Road to Diastolic Heart Failure: Diastolic Heart Failure study (MEDIA-DHF). Sex differences in these proteins were assessed using adjusted logistic regression analyses. The associations between candidate proteins and cardiovascular (CV) death or CV hospitalization (with sex interaction) were assessed using Cox regression models. Results: We found 9 proteins to be differentially expressed between female and male patients. Women expressed more LPL and PLIN1, which are markers of lipid metabolism; more LHB, IGFBP3, and IL1RL2 as markers of transcriptional regulation; and more Ep-CAM as marker of hemostasis. Women expressed less MMP-3, which is a marker associated with extracellular matrix organization; less NRP1, which is associated with developmental processes; and less ACE2, which is related to metabolism. Sex was not associated with the study outcomes (adj. HR 1.48, 95% CI 0.83-2.63), p = 0.18. Conclusion: In chronic HFpEF, assessing sex differences in a wide range of circulating proteins led to the identification of 9 proteins that were differentially expressed between female and male patients. These findings may help further investigations into potential pathophysiological processes contributing to HFpEF.