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Kruppel Like Factor 15 Expression is Associated with Cardiac Hypertrophy in an Experimental Model of Kidney Disease
Abstracts
for 4 weeks. Cardiac function and conduction were assessed by echocardiography and electrocardiogram (ECG), respectively. Molecular analyses were performed on heart tissue. Results: Ibrutinib treatment for 4 weeks reduced PI3K protein levels in the hearts of normal mice (∼40% decrease vs. vehicle controls, n=3-4/group, p<0.05), and ECG abnormalities (e.g. increased heart rate variability) were observed in >50% of mice. In the DCM model, ibrutinib treatment was associated with atrial enlargement (∼40% increase in atria weight/body weight compared to untreated DCM, n=5/group, p<0.05). Conclusion: In summary, ibrutinib reduces PI3K protein expression in the heart in vivo, and this is associated with cardiac abnormalities in normal mice and mice with DCM. http://dx.doi.org/10.1016/j.hlc.2016.06.181 181 Intramyocardial Delivery of miR-29a Improves Cardiac Function and Prevents Pathological Remodelling Following Myocardial Infarction Z. Ma ∗ , G. Quaife-Ryan, J. Lynch, C. McLellan, R. Mills, S. Phipps, J. Cooper-White, J. Hudson, E. Porrello The University of Queensland, Brisbane, Australia There is considerable interest in the therapeutic potential of microRNAs (miRNAs). While tremendous progress has been made in the development of miRNA inhibitors, efforts to increase the activity of miRNAs in vivo have proven more challenging and have traditionally relied on viral or nontargeted and expensive approaches, which are not readily transferrable to the clinic. The aim of our current study was to develop a simple, cheap and effective method for localised delivery of miRNAs to the infarct and border region, and to assess the therapeutic potential of miR-29, which was previously identified as a potent anti-fibrotic miRNA. Here, we explored a novel method for localised delivery of liposomeencapsulated miRNA mimics to the infarct and border region. Acute intramyocardial injection of miR-29a around the infarct border region was sufficient to mediate long-lasting cardioprotective effects, including reduced infarct size, reduced fibrosis, prevention of cardiac hypertrophy and improved cardiac function. Importantly, these therapeutic effects were achieved using a single injection of miRNA mimic at a dosage 1000 times lower than those required using systemic administration protocols. In addition to confirming the prototypical anti-fibrotic actions of miR-29, we also identified novel functions for miR-29 in the regulation of cardiomyocyte survival and the innate immune response. In addition, loss-of-function studies point to distinct gene regulatory functions of the miR29 family in the neonatal versus adult heart. These findings underscore the therapeutic potential of miR-29 mimicry and pave the way for future studies into the therapeutic benefits of miRNA delivery in the heart. http://dx.doi.org/10.1016/j.hlc.2016.06.182
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182 Kruppel Like Factor 15 Expression is Associated with Cardiac Hypertrophy in an Experimental Model of Kidney Disease S. Patel ∗ , E. Velkoska, L. Burrell The University of Melbourne, Australia Objective: Left ventricular hypertrophy (LVH) is prevalent in chronic kidney disease (CKD) and a major cause of cardiovascular morbidity and mortality. Treatment of LVH in CKD is based on blood pressure control. The Kruppel like factor 15 (KLF15) is expressed in the heart and acts as a repressor of cardiac hypertrophy and fibrosis. The role of cardiac KLF15 in the development of LVH in rats with CKD secondary to subtotal nephrectomy (STNx) or the effects of ACE inhibition on KLF15 levels has not been addressed previously. Design and method: Female Sprague Dawley rats underwent STNx and were treated for 4 weeks with either vehicle or the ACE inhibitor ramipril (oral 1 mg/kg). Control rats received vehicle (all groups, n=8/gp). Blood pressure and cardiac function were measured by catheterisation of the left ventricle. Results: STNx rats were hypertensive (P<0.05) with LVH and diastolic dysfunction, and had increased interstitial and perivascular fibrosis (all P<0.05). STNx rats had significantly reduced cardiac KLF15 gene and protein expression (P<0.05). In STNx (vs. STNx-vehicle), ramipril reduced blood pressure (P<0.01), improved LVH and perivascular fibrosis (P<0.01) and increased cardiac KLF15 protein (P<0.05) but did not significantly reduce interstitial fibrosis. Conclusion: This is the first report that cardiac KLF15 is down regulated in LVH associated with CKD. ACE inhibition increased KLF15 and reduced LVH but it had no effect on interstitial fibrosis. Studies are now needed to investigate new approaches that lead to further increases in KLF15 and reduce the adverse effects of LVH in CKD. http://dx.doi.org/10.1016/j.hlc.2016.06.183 183 Left Ventricular Long-Axis Function and Structure in Scleroderma R. Peverill 1,∗ , G. Ngian 2 , C. Mylrea 1 , J. Sahhar 2 1 Monash
Cardiovascular Research Centre, MonashHeart and Department of Medicine (School of Clinical Sciences at Monash Medical Centre), Monash University and Monash Health, Melbourne, Australia 2 Rheumatology Department, Monash Health, Melbourne, Australia Long-axis left ventricular (LV) dysfunction has been reported in subjects with scleroderma (SSc) with a normal ejection fraction (EF), but whether such dysfunction occurs in the absence of SSc-related conditions such as interstitial lung disease (ILD) and pulmonary hypertension (PH) is unknown. Neither is it known whether long-axis LV dysfunction might
for 4 weeks. Cardiac function and conduction were assessed by echocardiography and electrocardiogram (ECG), respectively. Molecular analyses were performed on heart tissue. Results: Ibrutinib treatment for 4 weeks reduced PI3K protein levels in the hearts of normal mice (∼40% decrease vs. vehicle controls, n=3-4/group, p<0.05), and ECG abnormalities (e.g. increased heart rate variability) were observed in >50% of mice. In the DCM model, ibrutinib treatment was associated with atrial enlargement (∼40% increase in atria weight/body weight compared to untreated DCM, n=5/group, p<0.05). Conclusion: In summary, ibrutinib reduces PI3K protein expression in the heart in vivo, and this is associated with cardiac abnormalities in normal mice and mice with DCM. http://dx.doi.org/10.1016/j.hlc.2016.06.181 181 Intramyocardial Delivery of miR-29a Improves Cardiac Function and Prevents Pathological Remodelling Following Myocardial Infarction Z. Ma ∗ , G. Quaife-Ryan, J. Lynch, C. McLellan, R. Mills, S. Phipps, J. Cooper-White, J. Hudson, E. Porrello The University of Queensland, Brisbane, Australia There is considerable interest in the therapeutic potential of microRNAs (miRNAs). While tremendous progress has been made in the development of miRNA inhibitors, efforts to increase the activity of miRNAs in vivo have proven more challenging and have traditionally relied on viral or nontargeted and expensive approaches, which are not readily transferrable to the clinic. The aim of our current study was to develop a simple, cheap and effective method for localised delivery of miRNAs to the infarct and border region, and to assess the therapeutic potential of miR-29, which was previously identified as a potent anti-fibrotic miRNA. Here, we explored a novel method for localised delivery of liposomeencapsulated miRNA mimics to the infarct and border region. Acute intramyocardial injection of miR-29a around the infarct border region was sufficient to mediate long-lasting cardioprotective effects, including reduced infarct size, reduced fibrosis, prevention of cardiac hypertrophy and improved cardiac function. Importantly, these therapeutic effects were achieved using a single injection of miRNA mimic at a dosage 1000 times lower than those required using systemic administration protocols. In addition to confirming the prototypical anti-fibrotic actions of miR-29, we also identified novel functions for miR-29 in the regulation of cardiomyocyte survival and the innate immune response. In addition, loss-of-function studies point to distinct gene regulatory functions of the miR29 family in the neonatal versus adult heart. These findings underscore the therapeutic potential of miR-29 mimicry and pave the way for future studies into the therapeutic benefits of miRNA delivery in the heart. http://dx.doi.org/10.1016/j.hlc.2016.06.182
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182 Kruppel Like Factor 15 Expression is Associated with Cardiac Hypertrophy in an Experimental Model of Kidney Disease S. Patel ∗ , E. Velkoska, L. Burrell The University of Melbourne, Australia Objective: Left ventricular hypertrophy (LVH) is prevalent in chronic kidney disease (CKD) and a major cause of cardiovascular morbidity and mortality. Treatment of LVH in CKD is based on blood pressure control. The Kruppel like factor 15 (KLF15) is expressed in the heart and acts as a repressor of cardiac hypertrophy and fibrosis. The role of cardiac KLF15 in the development of LVH in rats with CKD secondary to subtotal nephrectomy (STNx) or the effects of ACE inhibition on KLF15 levels has not been addressed previously. Design and method: Female Sprague Dawley rats underwent STNx and were treated for 4 weeks with either vehicle or the ACE inhibitor ramipril (oral 1 mg/kg). Control rats received vehicle (all groups, n=8/gp). Blood pressure and cardiac function were measured by catheterisation of the left ventricle. Results: STNx rats were hypertensive (P<0.05) with LVH and diastolic dysfunction, and had increased interstitial and perivascular fibrosis (all P<0.05). STNx rats had significantly reduced cardiac KLF15 gene and protein expression (P<0.05). In STNx (vs. STNx-vehicle), ramipril reduced blood pressure (P<0.01), improved LVH and perivascular fibrosis (P<0.01) and increased cardiac KLF15 protein (P<0.05) but did not significantly reduce interstitial fibrosis. Conclusion: This is the first report that cardiac KLF15 is down regulated in LVH associated with CKD. ACE inhibition increased KLF15 and reduced LVH but it had no effect on interstitial fibrosis. Studies are now needed to investigate new approaches that lead to further increases in KLF15 and reduce the adverse effects of LVH in CKD. http://dx.doi.org/10.1016/j.hlc.2016.06.183 183 Left Ventricular Long-Axis Function and Structure in Scleroderma R. Peverill 1,∗ , G. Ngian 2 , C. Mylrea 1 , J. Sahhar 2 1 Monash
Cardiovascular Research Centre, MonashHeart and Department of Medicine (School of Clinical Sciences at Monash Medical Centre), Monash University and Monash Health, Melbourne, Australia 2 Rheumatology Department, Monash Health, Melbourne, Australia Long-axis left ventricular (LV) dysfunction has been reported in subjects with scleroderma (SSc) with a normal ejection fraction (EF), but whether such dysfunction occurs in the absence of SSc-related conditions such as interstitial lung disease (ILD) and pulmonary hypertension (PH) is unknown. Neither is it known whether long-axis LV dysfunction might