Evidence map›Paper›PMID 37886847›Full record

ArticleCirculation2023

MDM2 Regulation of HIF Signaling Causes Microvascular Dysfunction in Hypertrophic Cardiomyopathy.

Puneeth Shridhar, Michael S Glennon, Soumojit Pal, Christina J Waldron, Ethan J Chetkof, Payel Basak, Nicolas G Clavere, Dipanjan Banerjee, Sebastien Gingras, Jason R Becker

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Circulation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
25citing papers in PubMed, 1 pooled it
7.5field-weighted citation impact, top 2% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

25 citing papers in PubMed, 1 synthesis or guideline pooled it, 34 citations in OpenAlex.

  1. Pooled it
  2. Review
  3. Article
  4. Article
  5. Review
  6. Article
  7. Article
  8. Article
  9. Article
  10. Article
  11. Article
  12. Ubiquitin E3 Ligases and p53 in Doxorubicin-Induced Cardiotoxicity.International journal of molecular sciences · 2025
    Review
  13. Article
  14. Article
  15. Article
  16. Article
  17. A Novel 6-bp Repeat Unit (6-bp RU) of the 13th Intron Within the ConservedInternational journal of molecular sciences · 2025
    Article
  18. Article
  19. Article
  20. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

10 authors at 1 institution in 1 country.

Puneeth ShridharDivision of Cardiology, Department of Medicine, and Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (P.S., M.S.G., S.P., C.J.W., E.J.C., P.B., N.C.G., D.B., J.R.B.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.
Michael S GlennonDivision of Cardiology, Department of Medicine, and Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (P.S., M.S.G., S.P., C.J.W., E.J.C., P.B., N.C.G., D.B., J.R.B.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.
Soumojit PalDivision of Cardiology, Department of Medicine, and Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (P.S., M.S.G., S.P., C.J.W., E.J.C., P.B., N.C.G., D.B., J.R.B.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.ORCID 0000-0002-3873-0450
Christina J WaldronDivision of Cardiology, Department of Medicine, and Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (P.S., M.S.G., S.P., C.J.W., E.J.C., P.B., N.C.G., D.B., J.R.B.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.
Ethan J ChetkofDivision of Cardiology, Department of Medicine, and Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (P.S., M.S.G., S.P., C.J.W., E.J.C., P.B., N.C.G., D.B., J.R.B.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.
Payel BasakDivision of Cardiology, Department of Medicine, and Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (P.S., M.S.G., S.P., C.J.W., E.J.C., P.B., N.C.G., D.B., J.R.B.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.
Nicolas G ClavereDivision of Cardiology, Department of Medicine, and Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (P.S., M.S.G., S.P., C.J.W., E.J.C., P.B., N.C.G., D.B., J.R.B.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.
Dipanjan BanerjeeDivision of Cardiology, Department of Medicine, and Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (P.S., M.S.G., S.P., C.J.W., E.J.C., P.B., N.C.G., D.B., J.R.B.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.ORCID 0000-0003-3331-958X
Sebastien GingrasDepartment of Immunology (S.G.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.ORCID 0000-0003-2607-8642
Jason R BeckerDivision of Cardiology, Department of Medicine, and Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute (P.S., M.S.G., S.P., C.J.W., E.J.C., P.B., N.C.G., D.B., J.R.B.), University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, PA.ORCID 0000-0002-2107-8179
University of Pittsburgh · US

Funding

Cell State Specific Modifiers of Pathological Cardiac RemodelingR01HL136824 · NHLBI · VANDERBILT UNIVERSITY MEDICAL CENTER · PI BECKER, JASON · 2017 to 2021
$2.0M
MDM2-HIF signaling in pathological ventricular remodelingR56HL160890 · NHLBI · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI BECKER, JASON · 2022 to 2022
$597k
NHLBI NIH HHS R01 HL136824NHLBI NIH HHS R56 HL160890
6 · The paper itself

Abstract

backgroundMicrovasculature dysfunction is a common finding in pathologic remodeling of the heart and is thought to play an important role in the pathogenesis of hypertrophic cardiomyopathy (HCM), a disease caused by sarcomere gene mutations. We hypothesized that microvascular dysfunction in HCM was secondary to abnormal microvascular growth and could occur independent of ventricular hypertrophy.

methodsWe used multimodality imaging methods to track the temporality of microvascular dysfunction in HCM mouse models harboring mutations in the sarcomere genes

resultsWe found that microvascular dysfunction in our HCM models occurred secondary to reduced myocardial capillary growth during the early postnatal time period and could occur before the onset of myocardial hypertrophy. We discovered that the E3 ubiquitin protein ligase MDM2 (murine double minute 2) dynamically regulates the protein stability of both HIF1α (hypoxia-inducible factor 1 alpha) and HIF2α (hypoxia-inducible factor 2 alpha)/EPAS1 (endothelial PAS domain protein 1) through canonical and noncanonical mechanisms. The resulting HIF imbalance leads to reduced proangiogenic gene expression during a key period of myocardial capillary growth. Reducing MDM2 protein levels by genetic or pharmacological methods normalized HIF protein levels and prevented the development of microvascular dysfunction in both HCM models.

conclusionsOur results show that sarcomere mutations induce cardiomyocyte MDM2 signaling during the earliest stages of disease, and this leads to long-term changes in the myocardial microenvironment.

Indexed as

Cardiomyopathy, HypertrophicProto-Oncogene Proteins c-mdm2AnimalsHypertrophyMiceMutationMyocardiumMyocytes, CardiacMyosin Heavy ChainsSarcomeresMyosin Heavy ChainsProto-Oncogene Proteins c-mdm2capillariescardiomyopathy, hypertrophichypoxiamyocardiummyosin heavy chainsproteasome endopeptidase complexsarcomere

Identifiers

PMID37886847
PMCPMC10691664
OpenAlexW4387966831

What OpenQuestion holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.