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BackgroundMaladaptive remodeling in pressure overload (PO)-induced left ventricular hypertrophy (LVH) may lead to heart failure. Major sex differences have been reported in this process. The steroid hormone 17β-estradiol, along with its receptors ERα and ERβ, is thought to be crucial for sex differences and is expected to be protective, but this may not hold true for males. Increasing evidence demonstrates a major role for microRNAs (miRNAs) in PO-induced LVH. However, little is known about the effects of biological sex and ERβ on cardiac miRNA regulation and downstream mitochondrial targets. We aimed at the analysis of proteins involved in mitochondrial metabolism testing the hypothesis that they are the target of sex-specific miRNA regulation.MethodsWe employed the transverse aortic constriction model in mice and assessed the levels of five mitochondrial proteins, i.e., Auh, Crat, Decr1, Hadha, and Ndufs4.ResultsWe found a significant decrease of the mitochondrial proteins primarily in the male overloaded heart compared with the corresponding control group. Following computational analysis to identify miRNAs putatively targeting these proteins, our in vitro experiments employing miRNA mimics demonstrated the presence of functional target sites for miRNAs in the 3′-untranslated region of the messenger RNAs coding for these proteins. Next, we assessed the levels of the functionally validated miRNAs under PO and found that their expression was induced only in the male overloaded heart. In contrast, there was no significant effect on miRNA expression in male mice with deficient ERβ.ConclusionWe put forward that the male-specific induction of miRNAs and corresponding downregulation of downstream protein targets involved in mitochondrial metabolism may contribute to sex-specific remodeling in PO-induced LVH.

Invasive fungal infections (IFI) have significantly increased over the past years due to advances in medical care for the at-risk immunocompromised population. IFI are often difficult to diagnose and manage, and can be associated with substantial morbidity and mortality. This study aims to contribute to understanding the etiology of invasive and subcutaneous fungal infections, their associated risk factors, and to perceive the outcome of patients who developed invasive disease, raising awareness of these infections at a local level but also in a global context. A laboratory surveillance approach was conducted over a seven-year period and included: (i) cases of invasive and subcutaneous fungal infections caused by filamentous/dimorphic fungi, confirmed by either microscopy or positive culture from sterile samples, (ii) cases diagnosed as probable IFI according to the criteria established by EORTC/MSG when duly substantiated. Fourteen Portuguese laboratories were enrolled. Cases included in this study were classified according to the new consensus definitions of invasive fungal diseases (IFD) published in 2020 as follows: proven IFI (N = 31), subcutaneous fungal infection (N = 23). Those proven deep fungal infections (N = 54) totalized 71.1% of the total cases, whereas 28.9% were classified as probable IFI (N = 22). It was possible to identify the etiological fungal agent in 73 cases (96%). Aspergillus was the most frequent genera detected, but endemic dimorphic fungi represented 14.47% (N = 11) of the total cases. Despite the small number of cases, a high diversity of species were involved in deep fungal infections. This fact has implications for clinical and laboratory diagnosis, and on the therapeutic management of these infections, since different species, even within the same genus, can present diverse patterns of susceptibility to antifungals.

Sex differences (SD) in cardiovascular diseases are described and have been attributed to the effects of sex hormones, such as estrogen (E2). Our previous studies in a mouse model of pressure overload revealed SD in fibrosis and apoptosis related genes that were abolished in estrogen receptor β deficient (ERβ-/-) mice. Other studies focus on miRNA regulation by E2, but little is known about sex-specific regulation of miRNAs in heart diseases. We hypothesize that E2 and ERβ are regulators of miRNA expression in the heart potentially contributing to the molecular mechanism of SD observed in cardiovascular diseases. This project aims to identify SD in the expression of miRNAs in a 9-week transverse aortic constriction (TAC) model and the possible role of E2 and ERβ in their regulation in the heart. A Targetscan analysis of 80 sex-specific dysregulated genes in hypertrophy allowed identifying 157 different miRNAs that could target them. Based on their expression in the heart we selected 60 miRNAs for quantification by qRT-PCR. In WT mice, 23 miRNAs showed SD in their expression in hypertrophy, all of them showing a higher expression in males than in females. All these significant SD were abolished in ERβ-/- mice. A direct comparison of some of these miRNAs in WT and ERβ-/- female animals identified nine miRNAs significantly higher expressed in the knock-out animals (let-7e, miR-106b, miR-130a, miR-133a, miR-20a, miR-24, miR-27b, miR-29a and miR-378). In vitro studies performed using a female cardiomyocyte cell line (AC16) showed a down-regulation of eight of these miRNAs after a 48h treatment with E2, being the exception miR-133a. The latter showed however a down-regulation after 48h treatment with an ERβ specific agonist, as well as let-7e, miR-106b, miR-130a, miR-20a, miR-24, miR-27b and miR-29a. The effect of treatment with ERα was only visible as a down-regulation of miR-24, miR-29a and miR-378. The potential of these miRNAs having targets in the same pathway and acting in a synergistic way is still under investigation. ERβ is for the first time identified as a major regulator of miRNA expression in the heart. It may play an important role in determining SD in cardiac hypertrophy, being responsible for the inhibition of miRNA expression in the female heart.

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