- Email: [email protected]
A Novel Histone Deacetylase (HDAC) Inhibitor Attenuates Cardiac Dysfunction in the Setting of Pressure Overload Heart Failure
Abstracts
159
Sam Victoriab, Jeffrey Schumacherc, David Lefera, Traci Goodchilda
Joseph Kozlowskid, David J. Lefera,b
a Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA b Department of Vascular Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA c Department of Animal Care, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
a Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA b Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA, USA c Merck Research Labs, Rahway, NJ, USA d Merck Research Laboratories, Kenilworth, NJ, USA
Introduction: Critical limb ischemia (CLI) is a peripheral arterial disease (PAD) caused by atherosclerosis that results in obstructions in the arteries resulting in limited blood supply to organs other than the heart. CLI is further defined as reduced blood flow to the lower limb(s) resulting in pain, even at rest, with or without associated ulcers or gangrene. Patients with CLI have a 6-month risk (25-40%) of major amputation and an annual mortality of 20% (11). Surgical and catheter-based revascularization are the preferred approaches for CLI though many patients with CLI are poor candidates for revascularization. Additionally, even after successful revascularization, stenosis or failure of the graft often reoccur resulting in a need for the development of new treatments for patients with CLI who are not candidates for revascularization. Objective: We sought to determine whether a novel H2S prodrug, SG-1002, promotes peripheral revascularization and coronary artery vascular function in a clinically relevant swine model of CLI. Approach and Results: Current studies have shown hydrogen sulfide (H2S) has various cytoprotective and cardioprotective properties. This study evaluated the therapeutic potential of the H2S donor, SG-1002, for critical limb ischemia in a swine model. 7 days after miniswine CLI induction, animals (n =17) received placebo or H2S donor, SG-1002 (800 mg PO BID), for 35 days. We observed higher circulating levels of H2S (5.0 ± 1.2 uM verses 1.8 ± 0.50 uM; P b0.05), sulfane sulfur (10.6 ± 2.3 uM verses 2.6 ± 0.8 uM; Pb0.05), and nitrite (0.5 ± 0.05 uM verses 0.3 ± 0.03 uM; Pb0.005) in pigs treated with SG-1002 at Day 35. DSA revealed an increase (Pb0.05) in ischemic limb vessel number in the SG-1002 treated pigs (27.6 ± 1.6) compared to the placebo group (22.2 ± 1.8). SG-1002 treatment improved bradykinin relaxation response of the LAD (EC50: 6.49 ± 1.2 nM verses 2.52 ± 1.2 nM, Pb0.001) and the LCX (EC50: 2.58 ± 1.2 nM verses 7.36 ± 1.2 nM, Pb0.0001). SG-1002 treatment improved SUB P relaxation responses of the LAD (EC50: 0.08 ± 0.02 nM verses 0.22 ± 0.01 nM, Pb0.0001) and the LCX (EC50: 0.07 ± 0.01 nM verses 0.14 ± 0.01 nM, Pb0.001). SG-1002 treatment also improved SNP relaxation responses of the LAD (0.42 ± 0.01 uM verses 0.54 ± 0.01 μM, Pb0.05) and the LCX (EC50: 0.38 ± 0.01 uM verses 0.81 ± 0.01 μM, Pb0.0001) compared to placebo. Conclusions: Results of this study suggest that daily administration of the novel H2S prodrug, SG-1002, leads to an elevation in circulating metabolites for H2S and NO signaling. By investigating the effects of SG-1002 on coronary artery vascular function and angiogenesis in a clinically relevant swine model of CLI, we show that oral administration of a novel long-acting H2S prodrug improves coronary artery vascular reactivity and vessel growth via an NO-dependent mechanism.
doi:10.1016/j.yjmcc.2017.07.085
074 A Novel Histone Deacetylase (HDAC) Inhibitor Attenuates Cardiac Dysfunction in the Setting of Pressure Overload Heart Failure Chelsea Organa,b, Zhen Lia,b, Craig Zibilicha, Traci Goodchilda,b, Shubing Wangc, Kersten M. Smalld, Jeffrey Madwedd, Jian Liud,
Background: Histone deacetylases (HDACs) are a family of epigenetic regulator enzymes responsible for chromatin conformation and reversible protein acetylation. HDAC inhibitors have previously been shown to be cardioprotective in acute myocardial infarction and heart failure. HDAC inhibition is thought to attenuate cardiac remodeling and improve cardiac function by enhancing acetylation of sarcomeric proteins, suppressing autophagy and apoptosis, bolstering protective genes and inhibiting pro-inflammatory genes. Objective: We investigated the efficacy of a novel, orally active HDAC class I inhibitor, MRL-003, in a murine model of pressure overload induced heart failure. Methods and Results: All studies were performed in a fully blinded manner, data analysis was performed off site by independent statisticians, and data was only unblinded following completion of statistical analysis of all parameters. Mice (C57 BL6J) at age 8-10 weeks were subjected to transverse aortic constriction (TAC) to induce pressure overload heart failure. Cardiac function was monitored sequentially using echocardiography and terminal hemodynamic measurements were taken. At 3 weeks post-TAC 3 doses (10, 30, and 100 mg/kg/day) of MRL-003 were provided to the mice in a blinded manner in chow ad libitum for 13 weeks. MRL-003 (100 mg/kg/d) significantly improved left ventricular (LV) ejection fraction and LV chamber dimensions compared to TAC-vehicle. LV end-diastolic pressure (LVEDP) was significantly increased in the vehicle treated group compared to sham and there was no significant difference in LVEDP in mice treated with MRL-003 (100 mg/kg/d) compared to sham. Conclusion: HDAC inhibition with MRL-003 significantly improves cardiac function and remodeling in the setting of pressure overload heart failure. Further studies are warranted to assess the molecular changes associated with these functional improvements.
doi:10.1016/j.yjmcc.2017.07.086
075 Hypercholesterolemic LDLr Knockout Swine as a Clinically Relevant Model of Hypertension Amanda Rushinga, Amy Scarborougha, James Stephen Jenkinsb, John Reillyb, Seena Khosravia, Rishi Trivedia, David Polhemusa, Traci Goodchilda, David Lefera a
Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA b Ochsner Interventional Cardiology, Ochsner Medical Center, New Orleans, LA 70121, USA Introduction: Coronary artery atherosclerosis is the single largest killer of men and women in the United States. Mutations in the LDL receptor (LDLr) gene lead to hypercholesterolemia and are associated with elevated plasma levels of total and LDL cholesterol. Renal denervation (RDN) has recently been investigated in clinical trials as a possible therapeutic for hypertensive patients. Although the clinical trials showed no significant difference in the blood pressures in control and RDN patients, researchers have shown reduction in myocardial infarction injury in a hypertensive rat model. Although
159
Sam Victoriab, Jeffrey Schumacherc, David Lefera, Traci Goodchilda
Joseph Kozlowskid, David J. Lefera,b
a Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA b Department of Vascular Surgery, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA c Department of Animal Care, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA
a Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA, USA b Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA, USA c Merck Research Labs, Rahway, NJ, USA d Merck Research Laboratories, Kenilworth, NJ, USA
Introduction: Critical limb ischemia (CLI) is a peripheral arterial disease (PAD) caused by atherosclerosis that results in obstructions in the arteries resulting in limited blood supply to organs other than the heart. CLI is further defined as reduced blood flow to the lower limb(s) resulting in pain, even at rest, with or without associated ulcers or gangrene. Patients with CLI have a 6-month risk (25-40%) of major amputation and an annual mortality of 20% (11). Surgical and catheter-based revascularization are the preferred approaches for CLI though many patients with CLI are poor candidates for revascularization. Additionally, even after successful revascularization, stenosis or failure of the graft often reoccur resulting in a need for the development of new treatments for patients with CLI who are not candidates for revascularization. Objective: We sought to determine whether a novel H2S prodrug, SG-1002, promotes peripheral revascularization and coronary artery vascular function in a clinically relevant swine model of CLI. Approach and Results: Current studies have shown hydrogen sulfide (H2S) has various cytoprotective and cardioprotective properties. This study evaluated the therapeutic potential of the H2S donor, SG-1002, for critical limb ischemia in a swine model. 7 days after miniswine CLI induction, animals (n =17) received placebo or H2S donor, SG-1002 (800 mg PO BID), for 35 days. We observed higher circulating levels of H2S (5.0 ± 1.2 uM verses 1.8 ± 0.50 uM; P b0.05), sulfane sulfur (10.6 ± 2.3 uM verses 2.6 ± 0.8 uM; Pb0.05), and nitrite (0.5 ± 0.05 uM verses 0.3 ± 0.03 uM; Pb0.005) in pigs treated with SG-1002 at Day 35. DSA revealed an increase (Pb0.05) in ischemic limb vessel number in the SG-1002 treated pigs (27.6 ± 1.6) compared to the placebo group (22.2 ± 1.8). SG-1002 treatment improved bradykinin relaxation response of the LAD (EC50: 6.49 ± 1.2 nM verses 2.52 ± 1.2 nM, Pb0.001) and the LCX (EC50: 2.58 ± 1.2 nM verses 7.36 ± 1.2 nM, Pb0.0001). SG-1002 treatment improved SUB P relaxation responses of the LAD (EC50: 0.08 ± 0.02 nM verses 0.22 ± 0.01 nM, Pb0.0001) and the LCX (EC50: 0.07 ± 0.01 nM verses 0.14 ± 0.01 nM, Pb0.001). SG-1002 treatment also improved SNP relaxation responses of the LAD (0.42 ± 0.01 uM verses 0.54 ± 0.01 μM, Pb0.05) and the LCX (EC50: 0.38 ± 0.01 uM verses 0.81 ± 0.01 μM, Pb0.0001) compared to placebo. Conclusions: Results of this study suggest that daily administration of the novel H2S prodrug, SG-1002, leads to an elevation in circulating metabolites for H2S and NO signaling. By investigating the effects of SG-1002 on coronary artery vascular function and angiogenesis in a clinically relevant swine model of CLI, we show that oral administration of a novel long-acting H2S prodrug improves coronary artery vascular reactivity and vessel growth via an NO-dependent mechanism.
doi:10.1016/j.yjmcc.2017.07.085
074 A Novel Histone Deacetylase (HDAC) Inhibitor Attenuates Cardiac Dysfunction in the Setting of Pressure Overload Heart Failure Chelsea Organa,b, Zhen Lia,b, Craig Zibilicha, Traci Goodchilda,b, Shubing Wangc, Kersten M. Smalld, Jeffrey Madwedd, Jian Liud,
Background: Histone deacetylases (HDACs) are a family of epigenetic regulator enzymes responsible for chromatin conformation and reversible protein acetylation. HDAC inhibitors have previously been shown to be cardioprotective in acute myocardial infarction and heart failure. HDAC inhibition is thought to attenuate cardiac remodeling and improve cardiac function by enhancing acetylation of sarcomeric proteins, suppressing autophagy and apoptosis, bolstering protective genes and inhibiting pro-inflammatory genes. Objective: We investigated the efficacy of a novel, orally active HDAC class I inhibitor, MRL-003, in a murine model of pressure overload induced heart failure. Methods and Results: All studies were performed in a fully blinded manner, data analysis was performed off site by independent statisticians, and data was only unblinded following completion of statistical analysis of all parameters. Mice (C57 BL6J) at age 8-10 weeks were subjected to transverse aortic constriction (TAC) to induce pressure overload heart failure. Cardiac function was monitored sequentially using echocardiography and terminal hemodynamic measurements were taken. At 3 weeks post-TAC 3 doses (10, 30, and 100 mg/kg/day) of MRL-003 were provided to the mice in a blinded manner in chow ad libitum for 13 weeks. MRL-003 (100 mg/kg/d) significantly improved left ventricular (LV) ejection fraction and LV chamber dimensions compared to TAC-vehicle. LV end-diastolic pressure (LVEDP) was significantly increased in the vehicle treated group compared to sham and there was no significant difference in LVEDP in mice treated with MRL-003 (100 mg/kg/d) compared to sham. Conclusion: HDAC inhibition with MRL-003 significantly improves cardiac function and remodeling in the setting of pressure overload heart failure. Further studies are warranted to assess the molecular changes associated with these functional improvements.
doi:10.1016/j.yjmcc.2017.07.086
075 Hypercholesterolemic LDLr Knockout Swine as a Clinically Relevant Model of Hypertension Amanda Rushinga, Amy Scarborougha, James Stephen Jenkinsb, John Reillyb, Seena Khosravia, Rishi Trivedia, David Polhemusa, Traci Goodchilda, David Lefera a
Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA b Ochsner Interventional Cardiology, Ochsner Medical Center, New Orleans, LA 70121, USA Introduction: Coronary artery atherosclerosis is the single largest killer of men and women in the United States. Mutations in the LDL receptor (LDLr) gene lead to hypercholesterolemia and are associated with elevated plasma levels of total and LDL cholesterol. Renal denervation (RDN) has recently been investigated in clinical trials as a possible therapeutic for hypertensive patients. Although the clinical trials showed no significant difference in the blood pressures in control and RDN patients, researchers have shown reduction in myocardial infarction injury in a hypertensive rat model. Although