Prelamin A mediates myocardial inflammation in dilated and HIV-Associated cardiomyopathies

Daniel Brayson; Andrea Frustaci; Romina Verardo; Cristina Chimenti; Matteo Antonio Russo; Robert Hayward; Sadia Munir Ahmad; Gema Vizcay-barrena; Andrea Protti; Peter S. Zammit; Cristobal G. Dos Remedios; Elisabeth Ehler; Ajay M. Shah; Catherine M. Shanahan

doi:10.1172/jci.insight.126315

Prelamin A mediates myocardial inflammation in dilated and HIV-Associated cardiomyopathies

Daniel Brayson, Andrea Frustaci, Romina Verardo, Cristina Chimenti, Matteo Antonio Russo, Robert Hayward, Sadia Munir Ahmad, Gema Vizcay-barrena, Andrea Protti, Peter S. Zammit, Cristobal G. Dos Remedios, Elisabeth Ehler, Ajay M. Shah, Catherine M. Shanahan

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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.

Original language	English
Article number	e126315
Journal	JCI Insight
Volume	4
Issue number	22
Early online date	17 Oct 2019
DOIs	https://doi.org/10.1172/jci.insight.126315
Publication status	Published - 14 Nov 2019

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Prelamin A mediates inflammation in dilated and HIV associated cardiomyopathiesAccepted author manuscript, 6.23 MBLicence: CC BY

http://insight.jci.org/articles/view/126315

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Brayson, D., Frustaci, A., Verardo, R., Chimenti, C., Russo, M. A., Hayward, R., Ahmad, S. M., Vizcay-barrena, G., Protti, A., Zammit, P. S., Dos Remedios, C. G., Ehler, E., Shah, A. M., & Shanahan, C. M. (2019). Prelamin A mediates myocardial inflammation in dilated and HIV-Associated cardiomyopathies. JCI Insight, 4(22), [e126315]. https://doi.org/10.1172/jci.insight.126315

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title = "Prelamin A mediates myocardial inflammation in dilated and HIV-Associated cardiomyopathies",

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.",

author = "Daniel Brayson and Andrea Frustaci and Romina Verardo and Cristina Chimenti and Russo, {Matteo Antonio} and Robert Hayward and Ahmad, {Sadia Munir} and Gema Vizcay-barrena and Andrea Protti and Zammit, {Peter S.} and {Dos Remedios}, {Cristobal G.} and Elisabeth Ehler and Shah, {Ajay M.} and Shanahan, {Catherine M.}",

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AU - Brayson, Daniel

AU - Frustaci, Andrea

AU - Verardo, Romina

AU - Chimenti, Cristina

AU - Russo, Matteo Antonio

AU - Hayward, Robert

AU - Ahmad, Sadia Munir

AU - Vizcay-barrena, Gema

AU - Protti, Andrea

AU - Zammit, Peter S.

AU - Dos Remedios, Cristobal G.

AU - Ehler, Elisabeth

AU - Shah, Ajay M.

AU - Shanahan, Catherine M.

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N2 - 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.

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Prelamin A mediates myocardial inflammation in dilated and HIV-Associated cardiomyopathies

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