Sex-Dependent Mechanisms of Cell Death Modalities in Cardiovascular Disease

Despite currently available therapies, cardiovascular diseases (CVD) are among the leading causes of death globally. Biological sex is a critical determinant of the occurrence, progression and overall outcome of CVD. However, the underlying mechanisms are incompletely understood. A hallmark of CVD is cell death. Based on the inability of the human heart to regenerate, loss of functional cardiac tissue can lead to irreversible detrimental effects. Here, we summarize current knowledge on how biological sex affects cell death-related mechanisms in CVD. Initially, we discuss apoptosis and necrosis, but we specifically focus on the relatively newly recognized programmed necrosis-like processes: pyroptosis and necroptosis. We also discuss the role of 17β-estradiol (E2) in these processes, particularly in terms of inhibiting pyroptotic and necroptotic signaling. We put forward that a better understanding of the effects of biological sex and E2 might lead to the identification of novel targets with therapeutic potential.