Sustained activation of microglia in the hypothalamic PVN following myocardial infarction
- Dworak, Melissa, Stebbing, Martin, Kompa, Andrew, Rana, Indrajeetsinh, Krum, Henry, Badoer, Emilio
- Authors: Dworak, Melissa , Stebbing, Martin , Kompa, Andrew , Rana, Indrajeetsinh , Krum, Henry , Badoer, Emilio
- Date: 2012
- Type: Text , Journal article
- Relation: Autonomic Neuroscience Vol. 169, no. 2 (August 2012 2012), p. 70-76
- Full Text: false
- Reviewed:
- Description: Microglia are the immune cells in the central nervous system and can produce cytokines when they are activated by an insult or injury. In the present study, we investigated in detail the time frame of the activation of microglia in the hypothalamic paraventricular nucleus (PVN) following myocardial infarction in rats. Morphological changes and immunohistochemistry to detect CD11b (clone OX-42) were used to identify activated microglia. Compared to rats that had undergone sham surgical procedures, there was a significant increase of between 40 and 50% in the proportion of activated microglia in the PVN 4–16 weeks following myocardial infarction (P < 0.001, One way ANOVA). At 24 h or 1 week post myocardial infarction, however, there was no significant increase in the proportion of activated microglia. Echocardiography and haemodynamic parameters after myocardial infarction indicated significantly reduced left ventricular function. In conclusion, following myocardial infarction, activation of microglia in the PVN does not occur immediately but once manifested, activation is sustained. Thus, activated microglia may contribute to the chronic elevation in cytokine levels observed following myocardial infarction. Since cytokines elicit sympatho-excitatory effects when locally microinjected into the PVN, activated microglia may contribute to the mechanisms mediating the chronic increase in sympathetic nerve activity in animals with reduced left ventricular function induced following myocardial infarction.
- Description: C1
Microglia activation in the hypothalamic PVN following myocardial infarction
- Rana, Indrajeetsinh, Stebbing, Martin, Kompa, Andrew, Kelly, Darren, Krum, Henry, Badoer, Emilio
- Authors: Rana, Indrajeetsinh , Stebbing, Martin , Kompa, Andrew , Kelly, Darren , Krum, Henry , Badoer, Emilio
- Date: 2010
- Type: Text , Journal article
- Relation: Brain Research Vol. 1326, no. (April 2010 2010), p. 96-104
- Full Text: false
- Reviewed:
- Description: Following a myocardial infarction (MI), inflammatory cytokines are elevated in the brain, as well as in plasma, indicating that inflammation is occurring in the brain in addition to the periphery. Microglia are the immune cells in the central nervous system and can produce cytokines when they are activated by an insult or injury. In the present study, we investigated whether MI in rats induces activation of microglia in the brain. We used immunohistochemistry to detect CD11b (clone OX-42) and morphological changes to identify activated microglia. Compared to control rats that had undergone sham surgical procedures, there was a significant increase in activated microglia in the hypothalamic paraventricular nucleus (PVN) following myocardial infarction. Activated microglia were not observed in the ventral hypothalamus, adjacent to the PVN, nor in the cortex, indicating the response was not the result of a generalized inflammatory reaction in the brain. Echocardiography and haemodynamic parameters after myocardial infarction indicated that reduced left ventricular function but congestive heart failure had not developed. In conclusion, microglia are activated in the PVN but not in the adjacent hypothalamus following myocardial infarction. The activated microglia may contribute to the increased local production of pro-inflammatory cytokines observed in the PVN after myocardial infarction and resulting in reduced left ventricular function.
- Description: C1
Contribution of microRNA to pathological fibrosis in cardiorenal syndrome : Impact of uremic toxins
- Rana, Indrajeetsinh, Kompa, Andrew, Skommer, Joanna, Wang, Bing, Lekawanvijit, Suree, Kelly, Darren, Krum, Henry, Charchar, Fadi
- Authors: Rana, Indrajeetsinh , Kompa, Andrew , Skommer, Joanna , Wang, Bing , Lekawanvijit, Suree , Kelly, Darren , Krum, Henry , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Physiological Reports Vol. 3, no. 4 (2015), p. 1-15
- Full Text:
- Reviewed:
- Description: Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and micro- RNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis. © 2015 The Authors.
- Authors: Rana, Indrajeetsinh , Kompa, Andrew , Skommer, Joanna , Wang, Bing , Lekawanvijit, Suree , Kelly, Darren , Krum, Henry , Charchar, Fadi
- Date: 2015
- Type: Text , Journal article
- Relation: Physiological Reports Vol. 3, no. 4 (2015), p. 1-15
- Full Text:
- Reviewed:
- Description: Progressive reduction in kidney function in patients following myocardial infarction (MI) is associated with an increase in circulating uremic toxins levels leading to increased extracellular matrix deposition. We have recently reported that treatment with uremic toxin adsorbent AST-120 in rats with MI inhibits serum levels of uremic toxin indoxyl sulfate (IS) and downregulates expression of cardiac profibrotic cytokine transforming growth factor beta (TGF-β1). In this study, we examined the effect of uremic toxins post-MI on cardiac microRNA-21 and microRNA-29b expression, and also the regulation of target genes and matrix remodeling proteins involved in TGFβ1 and angiotensin II signaling pathways. Sixteen weeks after MI, cardiac tissues were assessed for pathological and molecular changes. The percentage area of cardiac fibrosis was 4.67 ± 0.17 in vehicle-treated MI, 2.9 ± 0.26 in sham, and 3.32 ± 0.38 in AST-120-treated MI, group of rats. Compared to sham group, we found a twofold increase in the cardiac expression of microRNA-21 and 0.5-fold decrease in microRNA-29b in heart tissue from vehicle-treated MI. Treatment with AST-120 lowered serum IS levels and attenuated both, cardiac fibrosis and changes in expression of these microRNAs observed after MI. We also found increased mRNA expression of angiotensin-converting enzyme (ACE) and angiotensin receptor 1a (Agtr1a) in cardiac tissue collected from MI rats. Treatment with AST-120 attenuated both, expression of ACE and Agtr1a mRNA. Exposure of rat cardiac fibroblasts to IS upregulated angiotensin II signaling and altered the expression of both microRNA-21 and micro- RNA-29b. These results collectively suggest a clear role of IS in altering microRNA-21 and microRNA-29b in MI heart, via a mechanism involving angiotensin signaling pathway, which leads to cardiac fibrosis. © 2015 The Authors.
Cardiomyocyte functional etiology in heart failure with preserved ejection fraction is distinctive - A new preclinical model
- Curl, Claire, Danes, Vennetia, Bell, James, Raaijmakers, Antonia, Ip, Wendy, Chandramouli, Chanchal, Harding, Tristan, Porrello, Enzo, Erickson, Jeffrey, Charchar, Fadi, Kompa, Andrew, Edgley, Amanda, Crossman, David, Soeller, Christian, Mellor, Kimberley, Kalman, Jonathan, Harrap, Stephen, Delbridge, Lea
- Authors: Curl, Claire , Danes, Vennetia , Bell, James , Raaijmakers, Antonia , Ip, Wendy , Chandramouli, Chanchal , Harding, Tristan , Porrello, Enzo , Erickson, Jeffrey , Charchar, Fadi , Kompa, Andrew , Edgley, Amanda , Crossman, David , Soeller, Christian , Mellor, Kimberley , Kalman, Jonathan , Harrap, Stephen , Delbridge, Lea
- Date: 2018
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 7, no. 11 (2018), p. 1-32
- Full Text:
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- Description: Background--Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. Methods and Results--The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca
- Authors: Curl, Claire , Danes, Vennetia , Bell, James , Raaijmakers, Antonia , Ip, Wendy , Chandramouli, Chanchal , Harding, Tristan , Porrello, Enzo , Erickson, Jeffrey , Charchar, Fadi , Kompa, Andrew , Edgley, Amanda , Crossman, David , Soeller, Christian , Mellor, Kimberley , Kalman, Jonathan , Harrap, Stephen , Delbridge, Lea
- Date: 2018
- Type: Text , Journal article
- Relation: Journal of the American Heart Association Vol. 7, no. 11 (2018), p. 1-32
- Full Text:
- Reviewed:
- Description: Background--Among the growing numbers of patients with heart failure, up to one half have heart failure with preserved ejection fraction (HFpEF). The lack of effective treatments for HFpEF is a substantial and escalating unmet clinical need-and the lack of HFpEF-specific animal models represents a major preclinical barrier in advancing understanding of HFpEF. As established treatments for heart failure with reduced ejection fraction (HFrEF) have proven ineffective for HFpEF, the contention that the intrinsic cardiomyocyte phenotype is distinct in these 2 conditions requires consideration. Our goal was to validate and characterize a new rodent model of HFpEF, undertaking longitudinal investigations to delineate the associated cardiac and cardiomyocyte pathophysiology. Methods and Results--The selectively inbred Hypertrophic Heart Rat (HHR) strain exhibits adult cardiac enlargement (without hypertension) and premature death (40% mortality at 50 weeks) compared to its control strain, the normal heart rat. Hypertrophy was characterized in vivo by maintained systolic parameters (ejection fraction at 85%-90% control) with marked diastolic dysfunction (increased E/E'). Surprisingly, HHR cardiomyocytes were hypercontractile, exhibiting high Ca
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