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Regulatory Functions of Rac1 Palmitoylation in Cardiac Hypertrophy and Cardiomyocyte Signaling
Regulatory Functions of Rac1 Palmitoylation in Cardiac Hypertrophy and Cardiomyocyte Signaling
상세정보
- 자료유형
- 학위논문 서양
- 최종처리일시
- 20260202105228
- ISBN
- 9798291566978
- DDC
- 574
- 저자명
- Teuber, James.
- 서명/저자
- Regulatory Functions of Rac1 Palmitoylation in Cardiac Hypertrophy and Cardiomyocyte Signaling
- 발행사항
- [Sl] : University of Michigan, 2025
- 발행사항
- Ann Arbor : ProQuest Dissertations & Theses, 2025
- 형태사항
- 139 p
- 주기사항
- Source: Dissertations Abstracts International, Volume: 87-03, Section: B.
- 주기사항
- Advisor: Brody, Matthew J.
- 학위논문주기
- Thesis (Ph.D.)--University of Michigan, 2025.
- 초록/해제
- 요약Cardiac hypertrophy is a common adaptation to cardiovascular stress and often a prelude to heart failure. S-palmitoylation, or S-acylation, is a reversible, post-translational lipid modification of cysteine residues that offers spatiotemporal control of the signaling activity of substrate proteins. While palmitoylation has been investigated and shown to be important in several disease states, the functions of this modification in regulation of hypertrophic signaling in cardiomyocytesremain poorly understood. In this dissertation, I have examined how palmitoylation of the protein Rac1 influences its signaling in cardiomyocytes and how this regulates pathological cardiac hypertrophy. Rac1, a Rho family small GTPase, is a molecular switch that has previously been shown to promote hypertrophic signaling in mice. We found that mutation of cysteine-178, the major palmitoylation site of Rac1, resulted in impaired Rac1 activation in cardiomyocytes yet induced mild cardiomyocyte/cardiac hypertrophy in vitro and in vivo. To address how palmitoylation regulates signaling in cardiomyocytes, we generated Rac1 conditional knock-in (Rac1cKI) mice with endogenous expression of a Rac1C178S mutant protein which we found exhibit normal cardiac structure and function with age. Unexpectedly, we found that Rac1cKI mice develop more severe cardiac hypertrophy and functional decompensation in response to multiple models of chronic hypertrophic stress, including AngII infusion, pressure overload, and transgenic angiotensin II (AngII) type 1 receptor (AT1R) expression. Mechanistically, we found that Rac1cKI hearts exhibited hyperphosphorylation of protein kinase A (PKA) substrates in response to chronic hypertrophic stress or acute adrenergic stimulation without alterations in PKA activity. Furthermore, Rac1cKI mice display reduced levels of Ppp2r3a which encodes the PR72 regulatory subunit of protein phosphatase 2A (PP2A), a negative regulator of PKA phospho-sites. Taken together, these data suggest that palmitoylation of Rac1 at cysteine-178 is required for proper cardiac stress adaptation through a mechanism involving regulation of PKA/PP2A signaling in response to adrenergic drive. Future studies stemming from this work will seek to delineate how palmitoylation of Rac1 directly or indirectly regulates PKA/PP2A signaling in cardiomyocytes.
- 일반주제명
- Cellular biology
- 일반주제명
- Pharmacology
- 일반주제명
- Molecular biology
- 일반주제명
- Biochemistry
- 키워드
- Rac1 activation
- 키워드
- S-palmitoylation
- 키워드
- S-acylation
- 키워드
- Cardiomyocytes
- 키워드
- Protein kinase A
- 기타저자
- University of Michigan Pharmacology
- 기본자료저록
- Dissertations Abstracts International. 87-03B.
- 전자적 위치 및 접속
- 로그인 후 원문을 볼 수 있습니다.
MARC
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■020 ▼a9798291566978
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■040 ▼aMiAaPQ▼cMiAaPQ
■0820 ▼a574
■1001 ▼aTeuber, James.
■24510▼aRegulatory Functions of Rac1 Palmitoylation in Cardiac Hypertrophy and Cardiomyocyte Signaling
■260 ▼a[Sl]▼bUniversity of Michigan▼c2025
■260 1▼aAnn Arbor▼bProQuest Dissertations & Theses▼c2025
■300 ▼a139 p
■500 ▼aSource: Dissertations Abstracts International, Volume: 87-03, Section: B.
■500 ▼aAdvisor: Brody, Matthew J.
■5021 ▼aThesis (Ph.D.)--University of Michigan, 2025.
■520 ▼aCardiac hypertrophy is a common adaptation to cardiovascular stress and often a prelude to heart failure. S-palmitoylation, or S-acylation, is a reversible, post-translational lipid modification of cysteine residues that offers spatiotemporal control of the signaling activity of substrate proteins. While palmitoylation has been investigated and shown to be important in several disease states, the functions of this modification in regulation of hypertrophic signaling in cardiomyocytesremain poorly understood. In this dissertation, I have examined how palmitoylation of the protein Rac1 influences its signaling in cardiomyocytes and how this regulates pathological cardiac hypertrophy. Rac1, a Rho family small GTPase, is a molecular switch that has previously been shown to promote hypertrophic signaling in mice. We found that mutation of cysteine-178, the major palmitoylation site of Rac1, resulted in impaired Rac1 activation in cardiomyocytes yet induced mild cardiomyocyte/cardiac hypertrophy in vitro and in vivo. To address how palmitoylation regulates signaling in cardiomyocytes, we generated Rac1 conditional knock-in (Rac1cKI) mice with endogenous expression of a Rac1C178S mutant protein which we found exhibit normal cardiac structure and function with age. Unexpectedly, we found that Rac1cKI mice develop more severe cardiac hypertrophy and functional decompensation in response to multiple models of chronic hypertrophic stress, including AngII infusion, pressure overload, and transgenic angiotensin II (AngII) type 1 receptor (AT1R) expression. Mechanistically, we found that Rac1cKI hearts exhibited hyperphosphorylation of protein kinase A (PKA) substrates in response to chronic hypertrophic stress or acute adrenergic stimulation without alterations in PKA activity. Furthermore, Rac1cKI mice display reduced levels of Ppp2r3a which encodes the PR72 regulatory subunit of protein phosphatase 2A (PP2A), a negative regulator of PKA phospho-sites. Taken together, these data suggest that palmitoylation of Rac1 at cysteine-178 is required for proper cardiac stress adaptation through a mechanism involving regulation of PKA/PP2A signaling in response to adrenergic drive. Future studies stemming from this work will seek to delineate how palmitoylation of Rac1 directly or indirectly regulates PKA/PP2A signaling in cardiomyocytes.
■590 ▼aSchool code: 0127.
■650 4▼aCellular biology
■650 4▼aPharmacology
■650 4▼aMolecular biology
■650 4▼aBiochemistry
■653 ▼aCardiac hypertrophy
■653 ▼aRac1 activation
■653 ▼aS-palmitoylation
■653 ▼aS-acylation
■653 ▼aCardiomyocytes
■653 ▼aProtein kinase A
■690 ▼a0419
■690 ▼a0379
■690 ▼a0307
■690 ▼a0487
■71020▼aUniversity of Michigan▼bPharmacology.
■7730 ▼tDissertations Abstracts International▼g87-03B.
■790 ▼a0127
■791 ▼aPh.D.
■792 ▼a2025
■793 ▼aEnglish
■85640▼uhttp://www.riss.kr/pdu/ddodLink.do?id=T17359868▼nKERIS▼z이 자료의 원문은 한국교육학술정보원에서 제공합니다.
