Presentation is loading. Please wait.

Presentation is loading. Please wait.

A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted  Jayan Nagendran, MD, Vikram.

Published byFrancka Dolinar Modified over 5 years ago

Similar presentations

Presentation on theme: "A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted  Jayan Nagendran, MD, Vikram."— Presentation transcript:

1 A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted  Jayan Nagendran, MD, Vikram Gurtu, BSc, David Z. Fu, BSc, Jason R.B. Dyck, PhD, Al Haromy, BSc, David B. Ross, MD, Ivan M. Rebeyka, MD, Evangelos D. Michelakis, MD  The Journal of Thoracic and Cardiovascular Surgery  Volume 136, Issue 1, Pages e3 (July 2008) DOI: /j.jtcvs Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

2 Figure 1 Differences in mitochondrial membrane potential between human RV and LV myocardium. A and B, Confocal microscopy images of acutely TMRM and Hoechst loaded normal RV and LV myocardium from patient 1 (A) and normal RV and RVH from Patients 3 and 6, respectively (B). C, Mean TMRM fluorescence from all patients expressed in fluorescence units per area (n = 2 RV, n = 2 LV, n = 8 RVH). The Journal of Thoracic and Cardiovascular Surgery  , e3DOI: ( /j.jtcvs ) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

3 Figure 2 Similar mitochondrial membrane potential differences in adult rat RV and LV myocardium, also exist in isolated adult rat RV and LV cardiomyocytes. A, Confocal microscopy images of adult rat RV and LV myocardium loaded with TMRM and Hoechst. B, Isolated adult rat RV and LV cardiomyocytes loaded with TMRM and Hoechst. Merge panels also show differential interference contrast (DIC) channel for cell surface details. C, Mean TMRM fluorescence from all rat myocardial samples (n = 17 RV, n = 17 LV; ∗P < .01 vs RV myocardium). Mean TMRM fluorescence for individual cardiomyocytes (n = 58 RV, n = 83 LV; ∗P < .01 vs RV cardiomyocytes). TMRM, Tetramethyl–rhodamine methyl ester; DAPI, 4,6-diamino-2-phenylindole. The Journal of Thoracic and Cardiovascular Surgery  , e3DOI: ( /j.jtcvs ) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

4 Figure 3 Mitochondrial membrane potential progressively increases with the development of pathologic RVH. Upper third, Pulmonary artery acceleration time (PAAT; hatched bars) progressively decreased from control to 14 days to 28 days after monocrotaline (MCT) injection, while this was mirrored by a subsequent increase in RV free wall thickness (solid bars);∗P < .01 versus control; †P < .01 versus RV 14 days after MCT injection. Middle third, Mean TMRM fluorescence from all rat RV myocardial samples with progression of RVH after MCT injection (n = 17 control RV, n = 5 RV 14 days after MCT injection, n = 11 RV 28 days after MCT injection; ∗P < .01 vs control; †P < .01 vs RV 14 days after MCT injection). Bottom third, Representative confocal images of RV myocardium loaded with TMRM and Hoechst. The Journal of Thoracic and Cardiovascular Surgery  , e3DOI: ( /j.jtcvs ) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

5 Figure 4 DCA and NFAT inhibition reverse the mitochondrial hyperpolarization seen in RV cardiomyocytes from physiologic (neonatal RV) and pathologic (phenylephrine-induced) hypertrophy in vitro. A, Representative confocal images of neonatal rat cardiomyocytes treated with vehicle, phenylephrine (PE), phenylephrine plus dichloroacetate (PE+DCA), or phenylephrine plus VIVIT (PE+VIVIT) and cultured for 48 hours before loading with TMRM and Hoechst. Mean TMRM fluorescence for individual cardiomyocytes (n > 140 cardiomyocytes per treatment; ∗P < .01 vs control; †P < .01 vs phenylephrine). B, Immunocytochemistry performed in fixed neonatal cardiomyocytes after phenylephrine or phenylephrine+VIVIT treatment show the prevention of nuclear factor of activated T lymphocytes (NFAT, red) translocation into the nucleus (blue) by VIVIT (n = 6 plates per group [>150 cells/plate]; ∗P < .01 vs control; †P < .01 vs phenylephrine). C, Isolated neonatal rat RV and LV cardiomyocytes treated with vehicle, DCA, or VIVIT and cultured for 48 hours before loading with TMRM and Hoechst. Mean TMRM fluorescence for individual cardiomyocytes (n = 473 LV, n = 449 RV; ∗P < .01 vs LV cardiomyocytes; †P < .01 vs control). The Journal of Thoracic and Cardiovascular Surgery  , e3DOI: ( /j.jtcvs ) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

6 Figure 5 Targeted metabolic modulation by dichloroacetate (DCA) acutely improves RV inotropy in the ex vivo modified Langendorff perfused heart. A, Schematic of the isolated perfused RV (Langendorff preparation) to measure developed pressure. B, Representative real-time traces of the developed pressures from the normal RV (upper) and 28 days after monocrotaline injection RVH (lower) before and after the addition of DCA into the perfusate (shaded area). Note the significant increase in developed pressure only in the RVH hearts with acute DCA treatment. C, Mean data showing that DCA increased developed pressure (delta pressure from baseline developed pressure) in a dose-dependent manner in the RVH (n = 5) but not the normal RV (n = 6), whereas both normal and hypertrophied RV responded similarly to isoproterenol (∗P < .01 vs normal RV). D, Coronary sinus effluent was collected on ice from the modified Langendorff perfusions 5 minutes after a steady baseline was established and 10 minutes after initiating perfusion with DCA and was analyzed for lactate concentration (n = 6 RV, n = 5 RVH; ∗P < .01 vs normal RV; †P < .01 vs baseline). The Journal of Thoracic and Cardiovascular Surgery  , e3DOI: ( /j.jtcvs ) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

7 Verification of cardiomyocyte cell type
Verification of cardiomyocyte cell type. Representative confocal microscopy image of isolated neonatal rat cardiomyocytes stained for myosin heavy chain (green) and DAPI (blue) to confirm the cell isolation methods were specific for attaining cardiomyocytes over fibroblasts and/or vascular cells, with more than 97% of cells staining positive for myosin heavy chain. The Journal of Thoracic and Cardiovascular Surgery  , e3DOI: ( /j.jtcvs ) Copyright © 2008 The American Association for Thoracic Surgery Terms and Conditions

Download ppt "A dynamic and chamber-specific mitochondrial remodeling in right ventricular hypertrophy can be therapeutically targeted  Jayan Nagendran, MD, Vikram."

Similar presentations

Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery  Shu-Hong.

Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery  Shu-Hong.
Intracellular Action of Matrix Metalloproteinase-2 Accounts for Acute Myocardial Ischemia and Reperfusion Injury by Wenjie Wang, Costas J. Schulze, Wilma.

Intracellular Action of Matrix Metalloproteinase-2 Accounts for Acute Myocardial Ischemia and Reperfusion Injury by Wenjie Wang, Costas J. Schulze, Wilma.
Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery  Shu-Hong.

Tracking cardiac engraftment and distribution of implanted bone marrow cells: Comparing intra-aortic, intravenous, and intramyocardial delivery  Shu-Hong.
Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis 

Transplantation of hypoxia-preconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis 
Novel approach with intratracheal administration of microgelatin hydrogel microspheres incorporating basic fibroblast growth factor for rescue of rats.

Novel approach with intratracheal administration of microgelatin hydrogel microspheres incorporating basic fibroblast growth factor for rescue of rats.
Epicardial infarct repair with basic fibroblast growth factor–enhanced CorMatrix-ECM biomaterial attenuates postischemic cardiac remodeling  Holly E.M.

Epicardial infarct repair with basic fibroblast growth factor–enhanced CorMatrix-ECM biomaterial attenuates postischemic cardiac remodeling  Holly E.M.
“Triplet” polycistronic vectors encoding Gata4, Mef2c, and Tbx5 enhances postinfarct ventricular functional improvement compared with singlet vectors 

“Triplet” polycistronic vectors encoding Gata4, Mef2c, and Tbx5 enhances postinfarct ventricular functional improvement compared with singlet vectors 
Multimodal evaluation of in vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells  Stephen L. Hendry, MD, Koen E.A.

Multimodal evaluation of in vivo magnetic resonance imaging of myocardial restoration by mouse embryonic stem cells  Stephen L. Hendry, MD, Koen E.A.
Hemodynamics and myocardial blood flow patterns after placement of a cardiac passive restraint device in a model of dilated cardiomyopathy  Jennifer A.

Hemodynamics and myocardial blood flow patterns after placement of a cardiac passive restraint device in a model of dilated cardiomyopathy  Jennifer A.
Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: Safety and efficacy studies 

Intramyocardial delivery of CD133+ bone marrow cells and coronary artery bypass grafting for chronic ischemic heart disease: Safety and efficacy studies 
Salusin-β contributes to vascular inflammation associated with pulmonary arterial hypertension in rats  Tao Xu, MS, Zhifei Zhang, MD, PhD, Ting Liu, MBBS,

Salusin-β contributes to vascular inflammation associated with pulmonary arterial hypertension in rats  Tao Xu, MS, Zhifei Zhang, MD, PhD, Ting Liu, MBBS,
Impaired glycolytic metabolism causes chondrocyte hypertrophy-like changes via promotion of phospho-Smad1/5/8 translocation into nucleus  T. Nishida,

Impaired glycolytic metabolism causes chondrocyte hypertrophy-like changes via promotion of phospho-Smad1/5/8 translocation into nucleus  T. Nishida,
Cell-based gene therapy modifies matrix remodeling after a myocardial infarction in tissue inhibitor of matrix metalloproteinase-3–deficient mice  Denis.

Cell-based gene therapy modifies matrix remodeling after a myocardial infarction in tissue inhibitor of matrix metalloproteinase-3–deficient mice  Denis.
A meta-analysis of comparative studies of endovascular versus open repair for blunt thoracic aortic injury  Hisato Takagi, MD, PhD, Norikazu Kawai, MD,

A meta-analysis of comparative studies of endovascular versus open repair for blunt thoracic aortic injury  Hisato Takagi, MD, PhD, Norikazu Kawai, MD,
Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell–derived cardiomyocytes  Jun Luo, MD, PhD, Matthew S. Weaver,

Targeting survival pathways to create infarct-spanning bridges of human embryonic stem cell–derived cardiomyocytes  Jun Luo, MD, PhD, Matthew S. Weaver,
Mechanism of myocardial ischemia with an anomalous left coronary artery from the right sinus of Valsalva  Carlo R. Bartoli, PhD, William B. Wead, PhD,

Mechanism of myocardial ischemia with an anomalous left coronary artery from the right sinus of Valsalva  Carlo R. Bartoli, PhD, William B. Wead, PhD,
The reduction of hemodynamic loading assists self-regeneration of the injured heart by increasing cell proliferation, inhibiting cell apoptosis, and inducing.

The reduction of hemodynamic loading assists self-regeneration of the injured heart by increasing cell proliferation, inhibiting cell apoptosis, and inducing.
Tetrandrine prevents monocrotaline-induced pulmonary arterial hypertension in rats through regulation of the protein expression of inducible nitric oxide.

Tetrandrine prevents monocrotaline-induced pulmonary arterial hypertension in rats through regulation of the protein expression of inducible nitric oxide.
Changfa Guo, MD, Husnain Kh. Haider, PhD, Winston S. N

Changfa Guo, MD, Husnain Kh. Haider, PhD, Winston S. N
Lung injury after simulated cardiopulmonary bypass in an isolated perfused rat lung preparation: Role of mitogen-activated protein kinase/Akt signaling.

Lung injury after simulated cardiopulmonary bypass in an isolated perfused rat lung preparation: Role of mitogen-activated protein kinase/Akt signaling.

Similar presentations

Ads by Google