Deletion of Interleukin-1ß Converting Enzyme Alters Mouse Cardiac Structure and Function.

Interleukin-1ß converting enzyme (ICE, caspase-1) is a thiol protease that cleaves the pro-inflammatory cytokine precursors of IL-1ß and IL-18 into active forms. Given the association between caspase-1 and cardiovascular pathology, we analyzed the hearts of ICE knockout (ICE KO) mice to test the hypothesis that caspase-1 plays a significant role in cardiac morphology and function. We characterized the histological and functional changes in the hearts of ICE KO mice compared to the Wild type. The cardiomyocytes from the neonatal ICE KO mice showed an impaired response to oxidative stress. Subsequently, the hearts from the ICE KO mice were hypertrophied, with a significant increase in the left ventricular and septal wall thickness and a greater LV mass/body weight ratio. The ICE KO mice hearts exhibited irregular myofibril arrangements and disruption of the cristae in the mitochondrial structure. Proapoptotic proteins that were significantly increased in the hearts of ICE KO versus the Wild type included pErk, pJNK, p53, Fas, Bax, and caspase 3. Further, the antiapoptotic proteins Bag-1 and Bcl-2 are activated in ICE KO hearts. Functionally, there was an increase in the left ventricular epicardial diameter and volume in ICE KO. In conclusion, our findings support the important role of caspase-1 in maintaining cardiac health; specifically, a significant decrease in caspase-1 is detrimental to the cardiovascular system.

17 beta-estradiol inhibits cardiac fibroblast growth through both subtypes of estrogen receptor.

The effect of 17 beta-estradiol (E2) on the proliferation of cardiac fibroblasts (CFs) remains controversial. This study investigated which subtype of estrogen receptor (ER), ER alpha or ER beta, mediated the effect of E2 on CF growth by the gain of function analysis using an adenovirus vector. One hundred nanomoles per liter of E2 attenuated DNA synthesis by up to 10%, and transactivated the estrogen-responsive element determined by luciferase assay in rat neonatal CFs. We constructed replication-deficient adenoviruses bearing the coding region of human ER alpha, ER beta, or the dominant-negative form of ER beta (designated AxCAER alpha, AxCAER beta, and AxCADNER beta, respectively). When CFs were infected with AxCAER alpha or AxCAER beta at multiplicity of infection of 20 or higher, DNA synthesis was decreased by 50% in response to E2 and the effect was abolished by co-infection with AxCADNER beta. Similarly, transcriptional activity of ER in CFs infected with AxCAER alpha or AxCAER beta was markedly enhanced and co-infection with AxCADNER beta abolished the effects. These results suggest that E2 inhibits CF growth and that both ER subtypes mediate the effect comparably and redundantly.