Prolactin, 16-kDa Prolactin, and Cathepsin D Cascade There appears to be a cascade involving oxidative stress, the prolactin-cleaving protease cathepsin D, and prolactin in the pathophysiology of PPCM.9
Markers of cellular oxidation rise during pregnancy and hence an efficient antioxidant defense mechanism in the maternal heart is crucial, especially late in pregnancy and in the postpartum period. Experimental data in a mouse model of PPCM (mice with cardiomyocyte-restricted Inhibitors,research,lifescience,medical deletion of STAT3, signal transducer and activator of transcription-3) suggest that defective antioxidant mechanism may be responsible for the development of PPCM. Reduction in STAT3 appears to be a trigger that leads to activation of cathepsin
D in the cardiomyocytes, which subsequently causes increased cleavage of prolactin into an antiangiogenic and proapoptotic 16-kDa isoform.9 The 16-kDa prolactin fragment has potentially detrimental cardiovascular actions that could play a role in the pathophysiology Inhibitors,research,lifescience,medical of PPCM. It has been shown to inhibit endothelial cell proliferation and migration, induce endothelial apoptosis and disrupt already formed capillary structures, promote vasoconstriction, and impair cardiomyocyte function. The functional role of an activated oxidative stress-cathepsin D-16-kDa prolactin cascade is supported by Inhibitors,research,lifescience,medical the observation that Inhibitors,research,lifescience,medical in mice, treatment with bromocriptine, an inhibitor of prolactin secretion, prevented the development of PPCM. Also, patients with PPCM have increased serum levels of activated cathepsin D, total prolactin, and cleaved 16-kDa prolactin fragment.11 Autoimmune Mechanism High titers of auto-antibodies against selected cardiac tissue proteins have been found in the majority of women with PPCM.12 Warraich et al. investigated the role of humoral immunity and showed that unlike the selective upregulation of Capmatinib molecular weight immunoglobulins of the G3 subclass (IgG3s) in DCM, class G and all subclass immunoglobulins against cardiac myosin heavy Inhibitors,research,lifescience,medical chain were raised in PPCM.13 Of the serological variables, IgG3s (immunoglobulins with proinflammatory
characteristics) discriminated NYHA functional status at diagnosis. IgG3-positive patients were in a higher NYHA class at initial presentation. Similarly, Ansari et al. investigated the role of fetal Casein kinase 1 microchimerism (fetal cells in maternal blood) in patients with PPCM. In a small sample of patients, the amount of male chromosomal DNA in maternal plasma was significantly greater in patients with PPCM than in control mothers without PPCM during the third trimester of pregnancy, which could theoretically lead to the initiation of an autoimmune myocarditis.14 Inflammation Serum markers of inflammation like C-reactive protein, soluble death marker SFAS/Apo 1, interferon-gamma, interleukin (IL)-6, and TNF all have shown to be elevated in PPCM.