Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin Detyrosination
Impaired contractility after myocardial infarction (MI) causes cardiogenic shock. MARK4 activity impairs contractility post-MI by increasing α-tubulin detyrosination. We assessed the impact of naringenin, a small-molecule MARK4 inhibitor, on contractility post-MI. Naringenin (Nar) was encapsulated i...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2024-12-01
|
| Series: | Applied Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2076-3417/14/24/11936 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1846105951930679296 |
|---|---|
| author | Noah Weingarten Amit Iyengar Jessica Dominic Danika Meldrum Andrew Belec Sara Guevara-Plunkett Rachel Wilson Joyce Ho Mrinal Patel Chaitanya Karimanasseri Ahmad Amirshaghaghi Daphne Nie Benjamin W. Lee Deborah M. Eaton Kenneth B. Margulies Zhiliang Cheng Andrew Tsourkas Pavan Atluri |
| author_facet | Noah Weingarten Amit Iyengar Jessica Dominic Danika Meldrum Andrew Belec Sara Guevara-Plunkett Rachel Wilson Joyce Ho Mrinal Patel Chaitanya Karimanasseri Ahmad Amirshaghaghi Daphne Nie Benjamin W. Lee Deborah M. Eaton Kenneth B. Margulies Zhiliang Cheng Andrew Tsourkas Pavan Atluri |
| author_sort | Noah Weingarten |
| collection | DOAJ |
| description | Impaired contractility after myocardial infarction (MI) causes cardiogenic shock. MARK4 activity impairs contractility post-MI by increasing α-tubulin detyrosination. We assessed the impact of naringenin, a small-molecule MARK4 inhibitor, on contractility post-MI. Naringenin (Nar) was encapsulated in PEG-PCL to augment bioavailability. Wistar rats were randomized to receive either MI + micellized naringenin (0.3 mg/kg) [MI-NarMic], MI + naringenin (0.3 mg/kg) in 1% DMSO [MI-NarDMSO], MI + empty micelle [MI-Mic], MI alone [MI-Untreated], or no MI [Sham]. MI was induced via left anterior descending artery ligation. Invasive hemodynamics with pressure–volume catheterization, cardiomyocyte contractility, and ventricular protein abundance were assessed one day post-MI. A total of 45 rats underwent hemodynamic assessment. MI-NarMic rats demonstrated decreased α-tubulin detyrosination relative to MI-Untreated rats (<i>p</i> < 0.05). Myocytes isolated from peri-infarct tissue had increased contraction and relaxation velocities in MI-NarMic versus MI-Untreated rats (both <i>p</i> < 0.0001). MI-NarMic rats had higher ejection fractions than MI-Mic and MI-Untreated rats (63 ± 3% v. 48 ± 5% vs. 39 ± 4%, <i>p</i> < 0.05) and similar levels to Sham (61 ± 1%, <i>p</i> = 0.97) and MI-NarDMSO (54 ± 5%) rats (<i>p</i> > 0.05). MI-Nar rats had greater stroke work and lower end-diastolic pressure and tau than MI-Untreated rats (all <i>p</i> < 0.05). Micellized naringenin is a translatable agent with the potential to rescue hemodynamics post-MI by inhibiting MARK4 and mitigating myocardial α-tubulin detyrosination. |
| format | Article |
| id | doaj-art-d5d677166b30456f9b1078d60cb624e1 |
| institution | Kabale University |
| issn | 2076-3417 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Applied Sciences |
| spelling | doaj-art-d5d677166b30456f9b1078d60cb624e12024-12-27T14:08:49ZengMDPI AGApplied Sciences2076-34172024-12-0114241193610.3390/app142411936Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin DetyrosinationNoah Weingarten0Amit Iyengar1Jessica Dominic2Danika Meldrum3Andrew Belec4Sara Guevara-Plunkett5Rachel Wilson6Joyce Ho7Mrinal Patel8Chaitanya Karimanasseri9Ahmad Amirshaghaghi10Daphne Nie11Benjamin W. Lee12Deborah M. Eaton13Kenneth B. Margulies14Zhiliang Cheng15Andrew Tsourkas16Pavan Atluri17Division of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USADepartment of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 S. 33rd St., Philadelphia, PA 19104, USADepartment of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 S. 33rd St., Philadelphia, PA 19104, USADivision of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USADivision of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USADivision of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania, 3400 Civic Center Blvd., Philadelphia, PA 19104, USADepartment of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 S. 33rd St., Philadelphia, PA 19104, USADepartment of Bioengineering, University of Pennsylvania, 240 Skirkanich Hall, 210 S. 33rd St., Philadelphia, PA 19104, USADivision of Cardiovascular Surgery, Department of Surgery, University of Pennsylvania, 3400 Spruce St., Philadelphia, PA 19104, USAImpaired contractility after myocardial infarction (MI) causes cardiogenic shock. MARK4 activity impairs contractility post-MI by increasing α-tubulin detyrosination. We assessed the impact of naringenin, a small-molecule MARK4 inhibitor, on contractility post-MI. Naringenin (Nar) was encapsulated in PEG-PCL to augment bioavailability. Wistar rats were randomized to receive either MI + micellized naringenin (0.3 mg/kg) [MI-NarMic], MI + naringenin (0.3 mg/kg) in 1% DMSO [MI-NarDMSO], MI + empty micelle [MI-Mic], MI alone [MI-Untreated], or no MI [Sham]. MI was induced via left anterior descending artery ligation. Invasive hemodynamics with pressure–volume catheterization, cardiomyocyte contractility, and ventricular protein abundance were assessed one day post-MI. A total of 45 rats underwent hemodynamic assessment. MI-NarMic rats demonstrated decreased α-tubulin detyrosination relative to MI-Untreated rats (<i>p</i> < 0.05). Myocytes isolated from peri-infarct tissue had increased contraction and relaxation velocities in MI-NarMic versus MI-Untreated rats (both <i>p</i> < 0.0001). MI-NarMic rats had higher ejection fractions than MI-Mic and MI-Untreated rats (63 ± 3% v. 48 ± 5% vs. 39 ± 4%, <i>p</i> < 0.05) and similar levels to Sham (61 ± 1%, <i>p</i> = 0.97) and MI-NarDMSO (54 ± 5%) rats (<i>p</i> > 0.05). MI-Nar rats had greater stroke work and lower end-diastolic pressure and tau than MI-Untreated rats (all <i>p</i> < 0.05). Micellized naringenin is a translatable agent with the potential to rescue hemodynamics post-MI by inhibiting MARK4 and mitigating myocardial α-tubulin detyrosination.https://www.mdpi.com/2076-3417/14/24/11936naringeninMARK4microtubuleinotropemyocardial infarction |
| spellingShingle | Noah Weingarten Amit Iyengar Jessica Dominic Danika Meldrum Andrew Belec Sara Guevara-Plunkett Rachel Wilson Joyce Ho Mrinal Patel Chaitanya Karimanasseri Ahmad Amirshaghaghi Daphne Nie Benjamin W. Lee Deborah M. Eaton Kenneth B. Margulies Zhiliang Cheng Andrew Tsourkas Pavan Atluri Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin Detyrosination Applied Sciences naringenin MARK4 microtubule inotrope myocardial infarction |
| title | Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin Detyrosination |
| title_full | Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin Detyrosination |
| title_fullStr | Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin Detyrosination |
| title_full_unstemmed | Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin Detyrosination |
| title_short | Micellized Naringenin Augments Hemodynamics After Myocardial Infarction by Suppressing Tubulin Detyrosination |
| title_sort | micellized naringenin augments hemodynamics after myocardial infarction by suppressing tubulin detyrosination |
| topic | naringenin MARK4 microtubule inotrope myocardial infarction |
| url | https://www.mdpi.com/2076-3417/14/24/11936 |
| work_keys_str_mv | AT noahweingarten micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT amitiyengar micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT jessicadominic micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT danikameldrum micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT andrewbelec micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT saraguevaraplunkett micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT rachelwilson micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT joyceho micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT mrinalpatel micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT chaitanyakarimanasseri micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT ahmadamirshaghaghi micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT daphnenie micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT benjaminwlee micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT deborahmeaton micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT kennethbmargulies micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT zhiliangcheng micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT andrewtsourkas micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination AT pavanatluri micellizednaringeninaugmentshemodynamicsaftermyocardialinfarctionbysuppressingtubulindetyrosination |