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

Brayson, Daniel; Frustaci, Andrea; Verardo, Romina; Chimenti, Cristina; Russo, Matteo Antonio; Hayward, Robert; Ahmad, Shahbaz; Vizcay‐Barrena, Gema; Protti, Andrea; Zammit, Peter S.; Remedios, Cristobal G. dos; Ehler, Elisabeth; Shah, Ajay M.; Shanahan, Catherine M.

doi:10.1172/jci.insight.126315

Cited by 32 publications

(27 citation statements)

References 53 publications

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“…Alterations in lamin-mediated regulation of AKT (protein kinase B)/mTOR (mammalian target of rapamycin) pathways, which influence the expression or localization of Connexin 43, could represent another potential mechanism for arrhythmogenicity [31]. To note, prelamin A accumulation has been shown to mediate myocardial inflammation, which could contribute to acquired or genetically-determined cardiomyopathies [32]. Finally, alterations in extracellular matrix leading to fibrosis were described in laminopathies affecting adipose tissue [33,34], the vascular wall [18] and/or heart muscle [35], and could participate in multitissular complications.…”

Section: Discussionmentioning

confidence: 99%

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Mosbah

Vatier

Boccara

et al. 2020

Cells

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Variants in LMNA, encoding A-type lamins, are responsible for laminopathies including muscular dystrophies, lipodystrophies, and progeroid syndromes. Cardiovascular laminopathic involvement is classically described as cardiomyopathy in striated muscle laminopathies, and arterial wall dysfunction and/or valvulopathy in lipodystrophic and/or progeroid laminopathies. We report unexpected cardiovascular phenotypes in patients with LMNA-associated lipodystrophies, illustrating the complex multitissular pathophysiology of the disease and the need for specific cardiovascular investigations in affected patients. A 33-year-old woman was diagnosed with generalized lipodystrophy and atypical progeroid syndrome due to the newly identified heterozygous LMNA p.(Asp136Val) variant. Her complex cardiovascular phenotype was associated with atherosclerosis, aortic valvular disease and left ventricular hypertrophy with rhythm and conduction defects.A 29-year-old woman presented with a partial lipodystrophy syndrome and a severe coronary atherosclerosis which required a triple coronary artery bypass grafting. She carried the novel heterozygous p.(Arg60Pro) LMNA variant inherited from her mother, affected with partial lipodystrophy and dilated cardiomyopathy. Different lipodystrophy-associated LMNA pathogenic variants could target cardiac vasculature and/or muscle, leading to complex overlapping phenotypes. Unifying pathophysiological hypotheses should be explored in several cell models including adipocytes, cardiomyocytes and vascular cells. Patients with LMNA-associated lipodystrophy should be systematically investigated with 24-h ECG monitoring, echocardiography and non-invasive coronary function testing.

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Section: Discussionmentioning

confidence: 99%

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Mosbah

Vatier

Boccara

et al. 2020

Cells

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“…Lamin A arises via proteolytic processing of its precursor, prelamin A, by the zinc metalloproteinase ZMPSTE24 [13]. Accumulation of unprocessed prelamin A has been evidenced in genetically mediated laminopathies such as Hutchinson-Gilford Progeria Syndrome (HGPS), Emery-Dreifuss muscular dystrophy (EDMD) and dilated cardiomyopathy (DCM), while also accumulating in response to pharmacological inhibition of ZMPSTE24 [14][15][16]. Many disease-causing mutations have been described in lamins A/C, but there is very little genotype-phenotype correlation and effects of single mutations are often pleiotropic, making mechanistic study challenging [17].…”

Section: The Mechanics Of Linc Complex Misregulation In Muscle Diseasementioning

confidence: 99%

“…We recently investigated the role of cardiomyocyte-specific prelamin A accumulation in mice. We found that mice developed rapid-onset cardiomyopathy, which was underpinned by DNA damage accumulation, elevated senescence markers and a profound inflammatory response [14]. Western blot analysis of LINC complex proteins found increases in an abundance of a number of LINC components such as nesprin 2 and SUN2, as well as the intermediate filament (IF) cytoskeletal protein desmin, which is known to link directly to the NE via the nesprin isoform nesprin 3.…”

Section: (B) the Impact Of Muscle Mechanobiology Upon Genome Integritymentioning

confidence: 99%

The nuclear envelope: LINCing tissue mechanics to genome regulation in cardiac and skeletal muscle

Piccus

Brayson

2020

Biol. Lett.

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Regulation of the genome is viewed through the prism of gene expression, DNA replication and DNA repair as controlled through transcription, chromatin compartmentalisation and recruitment of repair factors by enzymes such as DNA polymerases, ligases, acetylases, methylases and cyclin-dependent kinases. However, recent advances in the field of muscle cell physiology have also shown a compelling role for ‘outside-in’ biophysical control of genomic material through mechanotransduction. The crucial hub that transduces these biophysical signals is called the Linker of Nucleoskeleton and Cytoskeleton (LINC). This complex is embedded across the nuclear envelope, which separates the nucleus from the cytoplasm. How the LINC complex operates to mechanically regulate the many functions of DNA is becoming increasingly clear, and recent advances have provided exciting insight into how this occurs in cells from mechanically activated tissues such as skeletal and cardiac muscle. Nevertheless, there are still some notable shortcomings in our understanding of these processes and resolving these will likely help us understand how muscle diseases manifest at the level of the genome.

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“…In our cohort, we also found an association between the inflammation biomarker hs-CRP and the expression of ZMPSTE24 mRNA. In this regard, a recently published study links inhibition of ZMPSTE24 activity by protease treatment in HIV patients with increased levels of premature prelamin A mediating myocardial inflammation and HIV-associated cardiomyopathy [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

ZMPSTE24 Is Associated with Elevated Inflammation and Progerin mRNA

Messner

Ghadge

Maurer

et al. 2020

Cells

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Lamins are important filaments forming the inner nuclear membrane. Lamin A is processed by zinc metalloproteinase (ZMPSTE24). Failure to cleave a truncated form of prelamin A—also called progerin—causes Hutchinson–Gilford progeria syndrome a well-known premature aging disease. Minor levels of progerin are readily expressed in the blood of healthy individuals due to alternative splicing. Previously, we found an association of increased progerin mRNA with overweight and chronic inflammation (hs-CRP). Here, we aimed to elucidate correlations of ZMPSTE24, lamin A/C and progerin with the inflammatory marker hs-CRP. In this retrospective, cross-sectional study we analyzed blood samples from 110 heart failure patients for quantitative mRNA expression of ZMPSTE24, lamin A/C, progerin and hs-CRP protein. Spearman correlations and linear regression analyses including adjustments for age, gender and ejection fraction showed a significant positive correlation of lnprogerin with lnZMPSTE24 (n = 110; r = 0.33; p = 0.0004) and lnlamin A/C (n = 110; r = 0.82, p < 0.0001), whereas no association was observed between lnlamin A/C and lnZMPSTE24 expression. Further analyses showed a significant positive correlation of lnhs-CRP with lnZMPSTE24 (n = 110; r = 0.21; p = 0.01) and lnlamin A/C (n = 110; r = 0.24; p = 0.03). We conclude that chronic inflammation is associated with increased expression of ZMPSTE24 and lamin A/C mRNA. Both markers also positively correlate with increased expression of the premature aging marker progerin which may be linked to cardiovascular aging.

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

Cited by 32 publications

References 53 publications

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

Looking at New Unexpected Disease Targets in LMNA-Linked Lipodystrophies in the Light of Complex Cardiovascular Phenotypes: Implications for Clinical Practice

The nuclear envelope: LINCing tissue mechanics to genome regulation in cardiac and skeletal muscle

ZMPSTE24 Is Associated with Elevated Inflammation and Progerin mRNA

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