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Molecular Research on Cardiomyopathy
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Molecular Research on Cardiomyopathy

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 16904

Special Issue Editor

Dr. Cristi L. Galindo

E-Mail Website
Guest Editor
Department of Biology, Western Kentucky University, Bowling Green, KY 42101, USA
Interests: muscular dystrophy; Duchenne; BDNF; neuregulin; ErbB3; cardiac fibrosis; TrkB; skeletal muscle
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The field of cardiovascular medicine has broadened as technologies evolve. More importantly, clinically relevant discoveries have grown exponentially with genomics, improvements in stem cells, inter-organ and systemic approaches, and cardiotoxicity side-effects of cancer drugs and a variety of other therapeutics. It is becoming increasingly apparent that the heart is inexorably linked to multiple human disease conditions. As such, the molecular underpinnings of non-cardiac processes have emerged with new relevancy to cardiac disease. Contributions to this Special Issue will provide insights into novel mechanisms of action that contribute broadly to cardiomyopathies of multiple etiologies and suggest therapeutic interventions for meeting new challenges in heart health.

Dr. Cristi L. Galindo
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at mdpi.longhoe.net by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • cardiomyopathy
  • genomics
  • gene expression
  • myocytes
  • fibrosis

Related Special Issue

Published Papers (5 papers)

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Research

15 pages, 6896 KiB  
Article
Sex-Based Differences in Cardiac Gene Expression and Function in BDNF Val66Met Mice
by Marcus Negron, Jeffrey Kristensen, Van Thuan Nguyen, Lauren E. Gansereit, Frank J. Raucci, Julia L. Chariker, Aaron Heck, Imamulhaq Brula, Gabrielle Kitchen, Cassandra P. Awgulewitsch, Lin Zhong, Eric C. Rouchka, Simran Banga and Cristi L. Galindo
Int. J. Mol. Sci. 2021, 22(13), 7002; https://doi.org/10.3390/ijms22137002 - 29 Jun 2021
Cited by 1 | Viewed by 2700
Abstract
Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single [...] Read more.
Brain-derived neurotrophic factor (BDNF) is a pleiotropic neuronal growth and survival factor that is indispensable in the brain, as well as in multiple other tissues and organs, including the cardiovascular system. In approximately 30% of the general population, BDNF harbors a nonsynonymous single nucleotide polymorphism that may be associated with cardiometabolic disorders, coronary artery disease, and Duchenne muscular dystrophy cardiomyopathy. We recently showed that transgenic mice with the human BDNF rs6265 polymorphism (Val66Met) exhibit altered cardiac function, and that cardiomyocytes isolated from these mice are also less contractile. To identify the underlying mechanisms involved, we compared cardiac function by echocardiography and performed deep sequencing of RNA extracted from whole hearts of all three genotypes (Val/Val, Val/Met, and Met/Met) of both male and female Val66Met mice. We found female-specific cardiac alterations in both heterozygous and homozygous carriers, including increased systolic (26.8%, p = 0.047) and diastolic diameters (14.9%, p = 0.022), increased systolic (57.9%, p = 0.039) and diastolic volumes (32.7%, p = 0.026), and increased stroke volume (25.9%, p = 0.033), with preserved ejection fraction and fractional shortening. Both males and females exhibited lower heart rates, but this change was more pronounced in female mice than in males. Consistent with phenotypic observations, the gene encoding SERCA2 (Atp2a2) was reduced in homozygous Met/Met mice but more profoundly in females compared to males. Enriched functions in females with the Met allele included cardiac hypertrophy in response to stress, with down-regulation of the gene encoding titin (Tcap) and upregulation of BNP (Nppb), in line with altered cardiac functional parameters. Homozygous male mice on the other hand exhibited an inflammatory profile characterized by interferon-γ (IFN-γ)-mediated Th1 immune responses. These results provide evidence for sex-based differences in how the BDNF polymorphism modifies cardiac physiology, including female-specific alterations of cardiac-specific transcripts and male-specific activation of inflammatory targets. Full article
(This article belongs to the Special Issue Molecular Research on Cardiomyopathy)
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12 pages, 2705 KiB  
Article
Loss of Nnt Increases Expression of Oxidative Phosphorylation Complexes in C57BL/6J Hearts
by Jack L. Williams, Charlotte L. Hall, Eirini Meimaridou and Lou A. Metherell
Int. J. Mol. Sci. 2021, 22(11), 6101; https://doi.org/10.3390/ijms22116101 - 5 Jun 2021
Cited by 7 | Viewed by 2739
Abstract
Nicotinamide nucleotide transhydrogenase (NNT) is a proton pump in the inner mitochondrial membrane that generates reducing equivalents in the form of NAPDH, which can be used for anabolic pathways or to remove reactive oxygen species (ROS). A number of studies have linked NNT [...] Read more.
Nicotinamide nucleotide transhydrogenase (NNT) is a proton pump in the inner mitochondrial membrane that generates reducing equivalents in the form of NAPDH, which can be used for anabolic pathways or to remove reactive oxygen species (ROS). A number of studies have linked NNT dysfunction to cardiomyopathies and increased risk of atherosclerosis; however, biallelic mutations in humans commonly cause a phenotype of adrenal insufficiency, with rare occurrences of cardiac dysfunction and testicular tumours. Here, we compare the transcriptomes of the hearts, adrenals and testes from three mouse models: the C57BL/6N, which expresses NNT; the C57BL/6J, which lacks NNT; and a third mouse, expressing the wild-type NNT sequence on the C57BL/6J background. We saw enrichment of oxidative phosphorylation genes in the C57BL/B6J in the heart and adrenal, possibly indicative of an evolved response in this substrain to loss of Nnt. However, differential gene expression was mainly driven by mouse background with some changes seen in all three tissues, perhaps reflecting underlying genetic differences between the C57BL/B6J and -6N substrains. Full article
(This article belongs to the Special Issue Molecular Research on Cardiomyopathy)
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20 pages, 4719 KiB  
Article
TFEB Overexpression, Not mTOR Inhibition, Ameliorates RagCS75Y Cardiomyopathy
by Maengjo Kim, Linghui Lu, Alexey V. Dvornikov, **ao Ma, Yonghe Ding, ** Zhu, Timothy M. Olson, Xueying Lin and **aolei Xu
Int. J. Mol. Sci. 2021, 22(11), 5494; https://doi.org/10.3390/ijms22115494 - 23 May 2021
Cited by 14 | Viewed by 3478
Abstract
A de novo missense variant in Rag GTPase protein C (RagCS75Y) was recently identified in a syndromic dilated cardiomyopathy (DCM) patient. However, its pathogenicity and the related therapeutic strategy remain unclear. We generated a zebrafish RragcS56Y (corresponding to human RagC [...] Read more.
A de novo missense variant in Rag GTPase protein C (RagCS75Y) was recently identified in a syndromic dilated cardiomyopathy (DCM) patient. However, its pathogenicity and the related therapeutic strategy remain unclear. We generated a zebrafish RragcS56Y (corresponding to human RagCS75Y) knock-in (KI) line via TALEN technology. The KI fish manifested cardiomyopathy-like phenotypes and poor survival. Overexpression of RagCS75Y via adenovirus infection also led to increased cell size and fetal gene reprogramming in neonatal rat ventricle cardiomyocytes (NRVCMs), indicating a conserved mechanism. Further characterization identified aberrant mammalian target of rapamycin complex 1 (mTORC1) and transcription factor EB (TFEB) signaling, as well as metabolic abnormalities including dysregulated autophagy. However, mTOR inhibition failed to ameliorate cardiac phenotypes in the RagCS75Y cardiomyopathy models, concomitant with a failure to promote TFEB nuclear translocation. This observation was at least partially explained by increased and mTOR-independent physical interaction between RagCS75Y and TFEB in the cytosol. Importantly, TFEB overexpression resulted in more nuclear TFEB and rescued cardiomyopathy phenotypes. These findings suggest that S75Y is a pathogenic gain-of-function mutation in RagC that leads to cardiomyopathy. A primary pathological step of RagCS75Y cardiomyopathy is defective mTOR–TFEB signaling, which can be corrected by TFEB overexpression, but not mTOR inhibition. Full article
(This article belongs to the Special Issue Molecular Research on Cardiomyopathy)
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19 pages, 6601 KiB  
Article
Reversal of the Inflammatory Responses in Fabry Patient iPSC-Derived Cardiovascular Endothelial Cells by CRISPR/Cas9-Corrected Mutation
by Hui-Yung Song, Yi-** Yang, Yueh Chien, Wei-Yi Lai, Yi-Ying Lin, Shih-Jie Chou, Mong-Lien Wang, Chien-Ying Wang, Hsin-Bang Leu, Wen-Chung Yu and Chian-Shiu Chien
Int. J. Mol. Sci. 2021, 22(5), 2381; https://doi.org/10.3390/ijms22052381 - 27 Feb 2021
Cited by 12 | Viewed by 3159
Abstract
The late-onset type of Fabry disease (FD) with GLA IVS4 + 919G > A mutation has been shown to lead to cardiovascular dysfunctions. In order to eliminate variations in other aspects of the genetic background, we established the isogenic control of induced pluripotent [...] Read more.
The late-onset type of Fabry disease (FD) with GLA IVS4 + 919G > A mutation has been shown to lead to cardiovascular dysfunctions. In order to eliminate variations in other aspects of the genetic background, we established the isogenic control of induced pluripotent stem cells (iPSCs) for the identification of the pathogenetic factors for FD phenotypes through CRISPR/Cas9 genomic editing. We adopted droplet digital PCR (ddPCR) to efficiently capture mutational events, thus enabling isolation of the corrected FD from FD-iPSCs. Both of these exhibited the characteristics of pluripotency and phenotypic plasticity, and they can be differentiated into endothelial cells (ECs). We demonstrated the phenotypic abnormalities in FD iPSC-derived ECs (FD-ECs), including intracellular Gb3 accumulation, autophagic flux impairment, and reactive oxygen species (ROS) production, and these abnormalities were rescued in isogenic control iPSC-derived ECs (corrected FD-ECs). Microarray profiling revealed that corrected FD-derived endothelial cells reversed the enrichment of genes in the pro-inflammatory pathway and validated the downregulation of NF-κB and the MAPK signaling pathway. Our findings highlighted the critical role of ECs in FD-associated vascular dysfunctions by establishing a reliable isogenic control and providing information on potential cellular targets to reduce the morbidity and mortality of FD patients with vascular complications. Full article
(This article belongs to the Special Issue Molecular Research on Cardiomyopathy)
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13 pages, 1127 KiB  
Article
Energy Metabolites as Biomarkers in Ischemic and Dilated Cardiomyopathy
by Jan Haas, Karen S. Frese, Farbod Sedaghat-Hamedani, Elham Kayvanpour, Rewati Tappu, Rouven Nietsch, Oguz Firat Tugrul, Michael Wisdom, Carsten Dietrich, Ali Amr, Tanja Weis, Torsten Niederdränk, Michael P. Murphy, Thomas Krieg, Marcus Dörr, Uwe Völker, Jens Fielitz, Norbert Frey, Stephan B. Felix, Andreas Keller, Hugo A. Katus and Benjamin Mederadd Show full author list remove Hide full author list
Int. J. Mol. Sci. 2021, 22(4), 1999; https://doi.org/10.3390/ijms22041999 - 18 Feb 2021
Cited by 22 | Viewed by 4098
Abstract
With more than 25 million people affected, heart failure (HF) is a global threat. As energy production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic changes in ischemic- and non-ischemic HF by using a [...] Read more.
With more than 25 million people affected, heart failure (HF) is a global threat. As energy production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM (p = 1.7 × 10−6). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting enzymes of these pathways could also be found and validated in our second stage of metabolite assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades that potentially represent suitable intervention targets. Full article
(This article belongs to the Special Issue Molecular Research on Cardiomyopathy)
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