Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Cordero, Pablo; Parikh, Victoria N.; Chin, Elizabeth T; Erbilgin, Ayca; Gloudemans, Michael J.; Shang, Ching; Huang, Yong; Chang, Alex Chia Yu; Smith, Kevin S.; Dewey, Frederick E.; Zaleta, Kathia; Morley, Michael; Brandimarto, Jeff; Glazer, Nicole L.; Pavlović, Aleksandra; Zhao, Mingming; Moravec, Christine S.; Tang, W.H. Wilson; Skreen, Jamie; Malloy, Christine; Hannenhalli, Sridhar; Li, Hongzhe; Ritter, Scott; Li, Mingyao; Bernstein, Daniel; Connolly, Andrew J.; Hákonarson, Hákon; Lusis, Aldons J.; Margulies, Kenneth B.; DePaoli‐Roach, Anna A.; Montgomery, Stephen B.; Wheeler, Matthew T.; Cappola, Thomas P.; Ashley, Euan A.

doi:10.1038/s41467-019-10591-5

Cited by 25 publications

(31 citation statements)

References 55 publications

(62 reference statements)

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“…Although ACTN2 protein levels were similar in the patient compared to controls, ACTN2 transcription was higher in the patient ( Figure 1I ). To evaluate if ACTN2 is differentially expressed in DCM and heart failure, we compared ACTN2 expression levels in the left ventricle of 25 healthy individuals, 24 DCM patients, and 21 patients with ischemic heart disease from the MAGNet consortium 31, 32 . No difference in ACTN2 expression was observed in these samples ( Supplementary Figure 3 ).…”

Section: Resultsmentioning

confidence: 99%

Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms

Lindholm

Jimenez-Morales

Zhu

et al. 2020

Preprint

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Alpha-actinin 2 (ACTN2) anchors actin within cardiac sarcomeres. The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel ACTN2 mutations to reveal insights into the physiological function of ACTN2. Patient-derived iPSC-cardiomyocytes harboring ACTN2 protein-truncating variants were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc structure. In homozygous stop-gain cells, affinity-purification mass spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 and GJA1, two sarcolemma-associated proteins, that may lead to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing. Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of ACTN2 truncation as causative of disease.

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Section: Resultsmentioning

confidence: 99%

Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms

Lindholm

Jimenez-Morales

Zhu

et al. 2020

Preprint

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“…Cardiac hypertrophy and fibrosis could affect each other in the progression of heart failure 18 , 19 . However, interpretation of the detailed mechanism of cardiac remodeling and heart failure remains a challenge 20 , 21 . The dual-specificity phosphatases (DUSPs) family has been known to be engaged in cardiac pathophysiology 22 , 23 ; however, its effects differ with the stimulations and experimental conditions.…”

Section: Discussionmentioning

confidence: 99%

Dual-specificity Phosphatase 9 protects against Cardiac Hypertrophy by targeting ASK1

Jiang¹,

Ren²,

Guo³

et al. 2021

Int. J. Biol. Sci.

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The functions of dual-specificity phosphatase 9 (DUSP9) in hepatic steatosis and metabolic disturbance during nonalcoholic fatty liver disease were discussed in our prior study. However, its roles in the pathophysiology of pressure overload-induced cardiac hypertrophy remain to be illustrated. This study attempted to uncover the potential contributions and underpinning mechanisms of DUSP9 in cardiac hypertrophy. Utilizing the gain-and-loss-of-functional approaches of DUSP9 the cardiac phenotypes arising from the pathological, echocardiographic, and molecular analysis were quantified. The results showed increased levels of DUSP9 in hypertrophic mice heart and angiotensin II treated cardiomyocytes. In accordance with the results of cellular hypertrophy in response to angiotensin II, cardiac hypertrophy exaggeration, fibrosis, and malfunction triggered by pressure overload was evident in the case of cardiac-specific conditional knockout of DUSP9. In contrast, transgenic mice hearts with DUSP9 overexpression portrayed restoration of the hypertrophic phenotypes. Further explorations of molecular mechanisms indicated the direct interaction of DUSP9 with ASK1, which further repressed p38 and JNK signaling pathways. Moreover, blocking ASK1 with ASK1-specific inhibitor compensated the pro-hypertrophic effects induced by DUSP9 deficiency in cardiomyocytes. The main findings of this study suggest the potential of DUSP9 in alleviating cardiac hypertrophy at least partially by repressing ASK1, thereby looks promising as a prospective target against cardiac hypertrophy.

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“…Neonatal rat cardiomyocytes (NRCMs) were isolated from 1 to 3-day-old Sprague-Dawley (SD) neonatal rats as previously described [19]. Brie y, neonatal rat hearts were nely minced and placed together in 0.25 % trypsin.…”

Section: Methodsmentioning

confidence: 99%

Age-Related Changes in the Gut Microbiota Promote Atrial Fibrillation

Zhang¹,

Zhang²,

Luo³

et al. 2020

Preprint

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Background: Aging is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-associated diseases. However, whether age-associated gut microbial dysbiosis contributes to AF is still unknown. The aim of this study was to evaluate the effect of gut microbiota on the susceptibility of aging-induced AF and to elucidate the underlying mechanisms. Results: The gut microbiota profiling of fecal samples in aged (22-24 months old) and young (2-3 months old) rats was performed by 16S ribosomal RNA gene analysis. A rat model of fecal microbiota transplantation (FMT) was established for analyzing the possible role of age-associated gut microbial dysbiosis in AF. Here, we found that aging process led to marked shift of the microbiota spectrum. The microbiota in young rats following FMT resembled that of aged microbiota and transmitted the increased AF susceptibility by elevation of circulating lipopolysaccharide (LPS). The mechanism for LPS-driven atrial pro-arrhythmic action was dependent on the activation of atrial nucleotide binding and oligomerization domain-like receptor family pyrin domain-containing (NLRP3)-inflammasome. Inhibition of inflammasome by MCC950 resulted in lower atrial fibrosis and AF susceptibility. In addition, atrial fibrosis, plasma LPS concentration, plasma glucose to oral glucose tolerance test (OGTT), intestinal permeability, and gut pathology were significantly increased in elderly human subjects. Finally, altering the microbiota in aged recipient to resemble that of young restored the intestinal barrier dysfunction and LPS and impaired glucose tolerance, and the worse outcomes of aged dysbiosis on atrial fibrosis and AF susceptibility were abrogated. Conclusions: These data suggest that age-associated microbial dysbiosis induces circulating LPS and impairs glucose tolerance, and thereby promotes AF susceptibility through enhanced activity of atrial NLRP3-inflammasome.

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Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure

Cited by 25 publications

References 55 publications

Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms

Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms

Dual-specificity Phosphatase 9 protects against Cardiac Hypertrophy by targeting ASK1

Age-Related Changes in the Gut Microbiota Promote Atrial Fibrillation

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