Abstract P1171: Golgi Localized DHHC3 And DHHC7 Contribute To The Initiation Of The Cardiac Hypertrophy Response In Vivo

Lipid modifications provide a layer of control over cardiac signaling molecules, including small GTPases and heterotrimeric G-proteins. Lipidation of signaling factors often permits their preferential localization to intracellular membranes and organelles where they then activate downstream effectors. S-palmitoylation is a reversible lipid modification catalyzed by a family of 23 palmitoyl acyltransferases, which are characterized by a conserved zinc finger-like aspartate-histidine-histidine-cystine (zDHHC) domain. Although the importance of GTPase palmitoylation is appreciated, our understanding of enzyme-substrate specificity remains uncertain and how these enzymes regulate cardiac stress signaling and hypertrophy is unknown. To examine the roles of the cardiac-expressed zDHHCs, we overexpressed zDHHC3, 5, 6, 7 and 13 using adeno-associated viruses. Overexpression of membrane-localized zDHHC5, ER localized zDHHC6 or Golgi-localized zDHHC13 had no effect on cardiac function, while overexpression of zDHHC3 or zDHHC7 (both Golgi-localized) caused dilated hypertrophic cardiomyopathy. zDHHC3 and zDHHC7 expression were also upregulated in the heart in response to transverse aortic constriction. To gain a better understanding of the physiological role of zDHHC3 and zDHHC7 in the heart we utilized gene-deleted mice subjected to models of pathological hypertrophy. At baseline, neither single (zDHHC3 and zDHHC7) or double (zDHHC3/7) knockout mice exhibit alterations in cardiac function. Total levels of GTPase signaling proteins are unchanged, although both single and double knockout mice have reduced palmitoylation of Gαs and Rac1. In response to pressure overload, knockout of both zDHHC3/7 delayed hypertrophic progression at an early timepoint (1 week), although the response is unchanged at a late timepoint (8 weeks). We conclude that both zDHHC3 and 7 contribute to the initiation of cardiac hypertrophy but are not key regulators of hypertrophic signaling.