We first made the mechanistic connection between cardiac hypertrophy, apoptotic cardiomyocyte death, and progression to heart failure in 1998 (Proc Natl Acad Sci USA. 95:10140-10145, 1998, pdf) (Figure 1), and subsequently identified Bcl2 family member Nix as the critical transcriptionally-induced mitochondrial pathway effector of apoptosis in cardiac hypertrophy (Nat Med. 8:725-730, 2002, pdf).
Work in the laboratory that combined mechanistic studies of Nix and engineered Nix mutants in tissue culture with molecular and physiological studies of conditional and conventional gene knockout or conditional cardiac-specific transgenic mice has since described the exact role of Nix and related Bnip3 in cardiac remodeling after pressure overload hypertrophy and myocardial infarction injury. Ongoing work follows upon our recent observation that Nix is targeted in part to endoplasmic reticulum (ER) and mediates ER-mitochondrial cross talk that leads to programmed necrosis (J Clin Invest. 119:203-212, 2009, pdf).