RT Journal Article
SR Electronic
T1 Accumulation of prelamin A drives inflammation in the heart with implications for treatment of inherited and acquired cardiomyopathies
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 457044
DO 10.1101/457044
A1 Daniel Brayson
A1 Andrea Frustaci
A1 Romina Verardo
A1 Cristina Chimenti
A1 Matteo Antonio Russo
A1 Robert Hayward
A1 Sadia Munir Ahmad
A1 Gema Vizcay-Barrena
A1 Andrea Protti
A1 Peter S. Zammit
A1 Cristobal G. dos Remedios
A1 Elisabeth Ehler
A1 Ajay M. Shah
A1 Catherine M. Shanahan
YR 2018
UL http://biorxiv.org/content/early/2018/11/28/457044.abstract
AB Cardiomyopathies are complex heart muscle diseases that can be inherited e.g. dilated cardiomyopathy resulting from LMNA gene mutations, or acquired, e.g. cardiomyopathy associated with HIV. In both cases the lamin A precursor, prelamin A, may play a central role: mutations in LMNA and certain HIV protease inhibitors acting via the enzyme ZMPSTE24 both inhibit prelamin A processing. Firstly, we show that myocardial prelamin A accumulation occurs in both these cardiomyopathies in patients. Secondly, we developed a novel mouse model of cardiac specific prelamin A accumulation which mimicked tissue and molecular features of HIV associated cardiomyopathy, including inflammation. These findings: (1) confirm a central pathological role of prelamin A common to genetic and acquired cardiomyopathies; (2) have implications for the management of HIV patients with cardiac disease in whom protease inhibitors with low/no binding to ZMPSTE24 may be preferred; and (3) suggest that targeting inflammation may be a useful treatment strategy for some forms of inherited cardiomyopathy.