Simplified apoptotic cascades

Apoptosis is an evolutionarily conserved mode of cell death that is tightly regulated and critical for multicellular organism development and cellular homeostasis. Specific biochemical and morphological changes characterise cells undergoing apoptosis, and reflect the specificity in which activated apoptotic pathways follow. The two best-characterized apoptotic pathways are the extrinsic pathway and the intrinsic pathway, which involve cell surface death receptors and the mitochondria and endoplasmic reticulum respectively. Apoptotic stimuli lead to activation of either or both of these pathways, and involve sequential activation of different cysteine proteases (caspases), and in the case of the intrinsic pathway, activation of a family of Bcl-2 proteins that critically regulate cell death. Conversely, dis-inhibition of endogenous inhibitors is often required for effective apoptotic cell death. Furthermore, an interesting recurring protein-protein interaction within this framework of apoptotic cascades involves interactions between death domain motifs that are present on many of the regulatory proteins in both apoptotic pathways. Cardiomyocyte apoptosis has been demonstrated in human heart failure and in rodents, apoptosis itself directly causes dilated cardiomyopathy. Understanding the intricacies of apoptotic death pathways and determining the relevance of these to cardiomyopathy is therefore essential if cardiomyocyte apoptosis is to be a pharmacological target for heart failure therapy.