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Role of MDM2 in Hypertrophic Cardiomyopathy

Shridhar, Puneeth (2023) Role of MDM2 in Hypertrophic Cardiomyopathy. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Hypertrophic cardiomyopathy (HCM) is a disease associated with abnormal thickening of the heart muscle and is a common genetic cause of cardiomyopathy in humans. Abnormalities of the small caliber blood vessels of the heart or other organs is defined as microvascular dysfunction (MVD) and is a common pathological finding in humans with HCM. However, it remains unclear when microvascular dysfunction develops in HCM and the molecular mechanisms regulating this process. We have previously identified that activation of cardiomyocyte DNA damage response pathways occur during the earliest periods of heart remodeling in multiple murine models of HCM. Therefore, we hypothesized that microvascular dysfunction developed during the same time interval and could be regulated by DNA damage response pathways. We utilized multiple complementary methods to track myocardial capillary growth and function in murine models of HCM. We found that microvascular dysfunction occurred during the early postnatal period and was secondary to reduced myocardial capillary formation and not capillary regression. During this same interval, we discovered dynamic changes in the cardiomyocyte protein levels of hypoxia-inducible factors, HIF1α and HIF2α, which directly contributed to alterations in myocardial capillary growth. We identified that this HIF imbalance was secondary to changes in protein ubiquitination that were regulated by the DNA damage response protein, murine double minute 2 (MDM2). Targeting MDM2 using genetic or pharmacological approaches normalized HIF levels, and prevented the development of microvascular dysfunction in multiple HCM models. In conclusion, MDM2 plays a crucial role in the development of microvascular dysfunction in HCM.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Shridhar, Puneethpus8@pitt.edupus80000-0002-7270-4029
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBecker, Jason R.beckerj@pitt.edu
Committee MemberShroff, Sanjeev G.sshroff@pitt.edu
Committee MemberRoy, Parthapar19@pitt.edu
Committee MemberChan, Stephen Y.chansy@pitt.edu
Committee MemberJurczak, Michael J.jurczakm@pitt.edu
Date: 13 June 2023
Date Type: Publication
Defense Date: April 2023
Approval Date: 13 June 2023
Submission Date: 5 March 2023
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 90
Institution: University of Pittsburgh
Schools and Programs: Swanson School of Engineering > Bioengineering
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: microvascular dysfunction, hypertrophic cardiomyopathy, sarcomeric cardiomyopathy, hypertrophy, hypoxia inducible factors, murine double minute 2, coronary flow reserve, cardiomyocyte, left ventricle, heart.
Additional Information: Submitting the draft for ETD format review.
Date Deposited: 13 Jun 2023 14:18
Last Modified: 13 Jun 2023 14:18
URI: http://d-scholarship.pitt.edu/id/eprint/44384

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