Abstract
Cardiomyopathies are complex heart muscle diseases that can be inherited or acquired. Dilated cardiomyopathy can result from mutations in LMNA, encoding the nuclear intermediate filament proteins lamin A/C. Some LMNA mutations lead to accumulation of the lamin A precursor, prelamin A, which is disease causing in a number of tissues, yet its impact upon the heart is unknown. Here, we discovered myocardial prelamin A accumulation occurred in a case of dilated cardiomyopathy, and we show that a potentially novel mouse model of cardiac-specific prelamin A accumulation exhibited a phenotype consistent with inflammatory cardiomyopathy, which we observed to be similar to HIV-associated cardiomyopathy, an acquired disease state. Numerous HIV protease therapies are known to inhibit ZMPSTE24, the enzyme responsible for prelamin A processing, and we confirmed that accumulation of prelamin A occurred in HIV+ patient cardiac biopsies. These findings (a) confirm a unifying pathological role for prelamin A common to genetic and acquired cardiomyopathies; (b) have implications for the management of HIV patients with cardiac disease, suggesting protease inhibitors should be replaced with alternative therapies (i.e., nonnucleoside reverse transcriptase inhibitors); and (c) suggest that targeting inflammation may be a useful treatment strategy for certain forms of inherited cardiomyopathy.
Highlights
Mutations in the LMNA gene are commonly implicated in dilated cardiomyopathy (DCM) phenotypes [1], accounting for approximately 6% of all cases [2]
Global Zmpste24–/– mice suffer from systemic inflammation arising from noncanonical ataxia telangiectasia mutated (ATM)-dependent NF-κB signaling [32], and we showed that this pathway was activated locally in csPLA-Tg hearts at 4 weeks, making it likely that increases in senescence-associated secretory phenotype (SASP) factors are caused by activation of NF-κB
Ment of HIV-associated cardiomyopathy patients, for whom a change of therapy may have a beneficial outcome in the clinic
Summary
Mutations in the LMNA gene are commonly implicated in dilated cardiomyopathy (DCM) phenotypes [1], accounting for approximately 6% of all cases [2]. Investigation of in vivo mouse models harboring LMNA mutations associated with clinical DCM have identified a number of mechanisms associated with disease [3]. The LMNA gene produces 2 distinct proteins, lamin A and lamin C, which — together with the B-type lamins — form the nuclear lamina that sits adjacent to the inner nuclear membrane (INM) of the nuclear envelope (NE), on the nucleoplasmic side [8]. The lamina forms part of the linker of nucleoskeleton to cytoskeleton (LINC) complex, which mediates physical communication with the cytoplasmic environment, enabling rapid responses to physical cues, a process termed mechanotransduction [11]
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