Sex Differences in Cardiovascular Diseases: A Matter of Estrogens, Ceramides, and Sphingosine 1-Phosphate

Abstract

The medical community recognizes sex-related differences in pathophysiology and cardiovascular disease outcomes (CVD), culminating with heart failure. In general, pre-menopausal women tend to have a better prognosis than men. Explaining why this occurs is not a simple matter. For decades, sex hormones like estrogens (Es) have been identified as one of the leading factors driving these sex differences. Indeed, Es seem protective in women as their decline, during and after menopause, coincides with an increased CV risk and HF development. However, clinical trials demonstrated that E replacement in post-menopause women results in adverse cardiac events and increased risk of breast cancer. Thus, a deeper understanding of E-related mechanisms is needed to provide a vital gateway toward better CVD prevention and treatment in women. Of note, sphingolipids (SLs) and their metabolism are strictly related to E activities. Among the SLs, ceramide and sphingosine 1-phosphate play essential roles in mammalian physiology, particularly in the CV system, and appear differently modulated in males and females. In keeping with this view, here we explore the most recent experimental and clinical observations about the role of E and SL metabolism, emphasizing how these factors impact the CV system.

Keywords: cardiovascular; estrogens; sex differences; sphingolipids.

Figure 1

Schematic representation of sphingolipid metabolism. The de novo synthesis pathway begins in the cytosolic leaflet of the smooth endoplasmic reticulum (ER). It starts with the condensation of palmitoyl coenzyme A (CoA) and serine, followed by several enzymatic reactions (red arrows) leading to the formation of sphinganine, sphingosine (S) and then ceramide (Cer). Once generated, Cer is transported to the Golgi apparatus where it is converted to sphingomyelin (SM) by SM synthase (SMS). SM is then transported to the plasma membrane where under specific condition/stimulation, SM can be reconverted in Cer by sphingomyelinase (SMase) that is further transformed into S and with the help of sphingosine kinases (SKs) is phosphorylated, thus leading to the generation of the bioactive lipid S1-phosphate (S1P) that is transported outside the membrane. Of note, the production of S1P is also possible in the lysosomes (salvage pathway) where SM is converted into Cer and then S. The S1P generated in this pathway can be either transported outside the cells or is reconverted into S by S1P phosphatase (SPP). S is finally transformed into Cer by Cer synthase.

Figure 2

Potential effects of 17β-estradiol (E2) or phytoestrogen (PhE) therapy in postmenopausal women. E2 and PhEs bind to ERs and GPER, thus preserving Cer/S1P rheostat with a consequent beneficial effect on the cardiovascular system. The chemical structures were produced on https://chemdrawdirect.perkinelmer.cloud/js/sample/index.html, accessed on 1 January 2022.