St Boniface Hospital Research Center

Winnipeg, Canada

St Boniface Hospital Research Center

Winnipeg, Canada
Time filter
Source Type

Chowdhury S.K.R.,St Boniface Hospital Research Center | Smith D.R.,St Boniface Hospital Research Center | Fernyhough P.,St Boniface Hospital Research Center | Fernyhough P.,University of Manitoba
Neurobiology of Disease | Year: 2013

Diabetic neuropathy is a neurological complication of diabetes that causes significant morbidity and, because of the obesity-driven rise in incidence of type 2 diabetes, is becoming a major international health problem. Mitochondrial phenotype is abnormal in sensory neurons in diabetes and may contribute to the etiology of diabetic neuropathy where a distal dying-back neurodegenerative process is a key component contributing to fiber loss. This review summarizes the major features of mitochondrial dysfunction in neurons and Schwann cells in human diabetic patients and in experimental animal models (primarily exhibiting type 1 diabetes). This article attempts to relate these findings to the development of critical neuropathological hallmarks of the disease. Recent work reveals that hyperglycemia in diabetes triggers nutrient excess in neurons that, in turn, mediates a phenotypic change in mitochondrial biology through alteration of the AMP-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) signaling axis. This vital energy sensing metabolic pathway modulates mitochondrial function, biogenesis and regeneration. The bioenergetic phenotype of mitochondria in diabetic neurons is aberrant due to deleterious alterations in expression and activity of respiratory chain components as a direct consequence of abnormal AMPK/PGC-1α signaling. Utilization of innovative respirometry equipment to analyze mitochondrial function of cultured adult sensory neurons from diabetic rodents shows that the outcome for cellular bioenergetics is a reduced adaptability to fluctuations in ATP demand. The diabetes-induced maladaptive process is hypothesized to result in exhaustion of the ATP supply in the distal nerve compartment and induction of nerve fiber dissolution. The role of mitochondrial dysfunction in the etiology of diabetic neuropathy is compared with other types of neuropathy with a distal dying-back pathology such as Friedreich ataxia, Charcot-Marie-Tooth disease type 2 and human immunodeficiency virus-associated distal-symmetric neuropathy. © 2012 Elsevier Inc.

Muller A.L.,St Boniface Hospital Research Center | Dhalla N.S.,University of Manitoba
Heart Failure Reviews | Year: 2012

It is believed that cardiac remodeling due to geometric and structural changes is a majormechanism for the progression of heart failure in different pathologies including hypertension, hypertrophic cardiomyopathy, dilated cardiomyopathy, diabetic cardiomyopathy, and myocardial infarction. Increases in the activities of proteolytic enzymes such as matrix metalloproteinases, calpains, cathepsins, and caspases contribute to the process of cardiac remodeling. In addition to modifying the extracellular matrix, both matrix metalloproteinases and cathepsins have been shown to affect the activities of subcellular organelles in cardiomyocytes. The activation of calpains and caspases has been identified to induce subcellular remodeling in failing hearts. Proteolytic activities associated with different proteins including caspases, calpain, and the ubiquitin-proteasome systemhave been shown to be involved in cardiomyocyte apoptosis,which is an integral part of cardiac remodeling. This article discusses and compares how the activities of various proteases are involved in different cardiac abnormalitieswith respect to alterations in apoptotic pathways, cardiac remodeling, and cardiac dysfunction. An imbalance appears to occur between the activities of some proteases and their endogenous inhibitors in various types of hypertrophied and failing hearts, and this is likely to further accentuate subcellular remodeling and cardiac dysfunction.The importance of inhibiting the activities of both extracellular and intracellular proteases specific to distinct etiologies, in attenuating cardiac remodeling and apoptosis as well as biochemical changes of subcellular organelles, in heart failure has been emphasized. It is suggested that combination therapy to inhibit different proteases may prove useful for the treatment of heart failure. © 2011 Springer Science+Business Media, LLC.

Jackson A.C.,University of Manitoba | Kammouni W.,University of Manitoba | Fernyhough P.,St Boniface Hospital Research Center | Fernyhough P.,University of Manitoba
Advances in Virus Research | Year: 2011

Recent studies in an experimental model of rabies indicated that there are major structural changes in the brain involving neuronal processes that are associated with severe clinical disease. Cultured adult mouse dorsal root ganglion (DRG) neurons are a good in vitro model for studying the mechanisms involved in rabies virus-induced degeneration of neurites (axons) because, unlike other neuronal cell types, these neurons are fairly permissive to rabies virus infection. DRG neurons infected with the challenge virus standard-11 (CVS) strain of rabies virus show axonal swellings and immunostaining for 4-hydroxy-2-nonenal (4-HNE), indicating evidence of lipid peroxidation associated with oxidative stress, and also reduced axonal growth in comparison with mock-infected DRG neurons. Treatment with the antioxidant N-acetyl cysteine prevented the reduction in axonal outgrowth that occurred with CVS infection. The axonal swellings with 4-HNE-labeled puncta were found to be associated with aggregations of actively respiring mitochondria. We postulate that rabies virus infection likely induces mitochondrial dysfunction resulting in oxidative stress and degenerative changes involving neuronal processes. This mitochondrial dysfunction may be the result of either direct or indirect effects of the virus on the mitochondrial electron-transport chain or it may occur through other mechanisms. Further investigations are needed to gain a better understanding of the basic mechanisms involved in the oxidative damage associated with rabies virus infection. This information may prove helpful in the design of future therapeutic effects for this dreaded ancient disease. © 2011 Elsevier Inc.

Fernyhough P.,University of Manitoba | Fernyhough P.,St Boniface Hospital Research Center | Calcutt N.A.,University of California at San Diego
Cell Calcium | Year: 2010

Abnormal neuronal calcium (Ca2+) homeostasis has been implicated in numerous diseases of the nervous system. The pathogenesis of two increasingly common disorders of the peripheral nervous system, namely neuropathic pain and diabetic polyneuropathy, has been associated with aberrant Ca2+ channel expression and function. Here we review the current state of knowledge regarding the role of Ca2+ dyshomeostasis and associated mitochondrial dysfunction in painful and diabetic neuropathies. The central impact of both alterations of Ca2+ signalling at the plasma membrane and also intracellular Ca2+ handling on sensory neurone function is discussed and related to abnormal endoplasmic reticulum performance. We also present new data highlighting sub-optimal axonal Ca2+ signalling in diabetic neuropathy and discuss the putative role for this abnormality in the induction of axonal degeneration in peripheral neuropathies. The accumulating evidence implicating Ca2+ dysregulation in both painful and degenerative neuropathies, along with recent advances in understanding of regional variations in Ca2+ channel and pump structures, makes modulation of neuronal Ca2+ handling an increasingly viable approach for therapeutic interventions against the painful and degenerative aspects of many peripheral neuropathies. © 2009 Elsevier Ltd. All rights reserved.

Chowdhury S.K.R.,St Boniface Hospital Research Center | Dobrowsky R.T.,University of Kansas | Fernyhough P.,St Boniface Hospital Research Center | Fernyhough P.,University of Manitoba
Mitochondrion | Year: 2011

Diabetic neuropathy is a major complication of diabetes that results in the progressive deterioration of the sensory nervous system. Mitochondrial dysfunction has been proposed to play an important role in the pathogenesis of the neurodegeneration observed in diabetic neuropathy. Our recent work has shown that mitochondrial dysfunction occurs in dorsal root ganglia (DRG) sensory neurons in streptozotocin (STZ) induced diabetic rodents. In neurons, the nutrient excess associated with prolonged diabetes may trigger a switching off of AMP kinase (AMPK) and/or silent information regulator T1 (SIRT1) signaling leading to impaired peroxisome proliferator-activated receptor γ coactivator-1 (PGC-1α) expression/activity and diminished mitochondrial activity. This review briefly summarizes the alterations of mitochondrial function and proteome in sensory neurons of STZ-diabetic rodents. We also discuss the possible involvement of AMPK/SIRT/PGC-1α pathway in other diabetic models and different tissues affected by diabetes. © 2011 Elsevier B.V. and Mitochondria Research Society.

Fernyhough P.,St Boniface Hospital Research Center | Fernyhough P.,University of Manitoba
Current Diabetes Reports | Year: 2015

Diabetic neuropathy is a dying back neurodegenerative disease of the peripheral nervous system where mitochondrial dysfunction has been implicated as an etiological factor. Diabetes (type 1 or type 2) invokes an elevation of intracellular glucose concentration simultaneously with impaired growth factor support by insulin, and this dual alteration triggers a maladaptation in metabolism of adult sensory neurons. The energy sensing pathway comprising the AMP-activated protein kinase (AMPK)/sirtuin (SIRT)/peroxisome proliferator-activated receptor-γ coactivator α (PGC-1α) signaling axis is the target of these damaging changes in nutrient levels, e.g., induction of nutrient stress, and loss of insulin-dependent growth factor support and instigates an aberrant metabolic phenotype characterized by a suppression of mitochondrial oxidative phosphorylation and shift to anaerobic glycolysis. There is discussion of how this loss of mitochondrial function and transition to overreliance on glycolysis contributes to the diminishment of collateral sprouting and axon regeneration in diabetic neuropathy in the context of the highly energy-consuming nerve growth cone. © 2015, Springer Science+Business Media New York.

Dent M.R.,St Boniface Hospital Research Center | Tappia P.S.,University of Manitoba | Dhalla N.S.,St Boniface Hospital Research Center
Journal of Cardiac Failure | Year: 2010

Background: This study examined the sex differences for hemodynamic and echocardiographic changes in hypertrophied and failing hearts induced by arteriovenous (AV) shunt. Methods and Results: Echocardiographic and hemodynamic alterations were determined in male and female rats at 4 and 16 weeks after AV shunt. Ovariectomized females treated with estrogen for 16 weeks post-AV shunt were also used. Both genders developed cardiac hypertrophy at 4 and 16 weeks post-AV shunt; however, the increase in cardiac muscle mass was greater in females than males at 16 weeks. At 4 weeks post-AV shunt, increases in ventricular dimensions and left ventricular end-diastolic pressure (LVEDP) as well as a decrease in fractional shortening occurred in males only. Unlike the females, the rates of pressure development (+dP/dt) and decay (-dP/dt) were depressed and LVEDP increased in male rats at 16 weeks post-AV shunt. An increase in cardiac output was seen in both genders, but this was more marked in the males at 4 and 16 weeks post-AV shunt. Although mRNA levels for ACE were increased in both male and female rats at 4 and 16 weeks, mRNA levels for angiotensin II type 1 receptor were increased in males at 16 weeks only. Furthermore, increases in plasma catecholamines were elevated in males but were decreased or unchanged in females at 16 weeks of AV shunt. LV internal diameters as well as depressed fractional shortening occurred in males whereas increases in posterior wall thickness were seen in the female rats at 16 weeks of AV shunt. Ovariectomy resulted in depressed +dP/dt, -dP/dt, and fractional shortening, whereas a marked increase in cardiac output as well as increased LVEDP and LV internal diameters were observed at 16 weeks post-AV shunt. Although treatment with 17-β estradiol normalized ±dP/dt, LVEDP remained elevated. Conclusion: Gender differences in cardiac function may be due to differences in the type of cardiac remodeling as a consequence of AV shunt. Furthermore, estrogen appears to play an important role in preventing cardiac dysfunction and adverse ventricular remodeling in female rats. © 2010 Elsevier Inc. All rights reserved.

Muller A.L.,St Boniface Hospital Research Center | Freed D.,University of Manitoba | Dhalla N.S.,St Boniface Hospital Research Center
Journal of Applied Physiology | Year: 2013

Previous studies have shown that ischemia-reperfusion (I/R) injury is associated with cardiac dysfunction and changes in sarcolemmal Na +-K+- ATPase subunits and activity. This study was undertaken to evaluate the role of proteases in these alterations by subjecting rat hearts to different times of global ischemia, as well as reperfusion after 45 min of ischemia. Decreases in Na+-K+-ATPase activity at 30-60 min of global ischemia were accompanied by augmented activities of both calpain and matrix metalloproteinases (MMPs) and depressed protein content of β1- and β2-subunits, without changes in α1- and α2- subunits of the enzyme. Compared with control values, the activities of both calpain and MMP-2 were increased, whereas the activity and protein content for all subunits of Na+-K+-ATPase were decreased upon reperfusion for 5-40 min, except that α1- and α2-subunit content was not depressed in 5 min I/R hearts. MDL28170, a calpain inhibitor, was more effective in attenuating the I/R-induced alterations in cardiac contracture, Na+-K+-ATPase activity, and α2-subunit than doxycycline, an MMP inhibitor. Incubation of control sarcolemma preparation with calpain, unlike MMP-2, depressed Na+-K+-ATPase activity and decreased α1-, α2-, and β2-subunits, without changes in the β1-subunit. These results support the view that activation of both calpain and MMP-2 are involved in depressing Na+-K+-ATPase activity and degradation of its subunits directly or indirectly in hearts subjected to I/R injury. Copyright © 2013 the American Physiological Society.

Biala A.K.,St Boniface Hospital Research Center | Dhingra R.,University of Manitoba | Kirshenbaum L.A.,University of Manitoba
Journal of Molecular and Cellular Cardiology | Year: 2015

Aging is a degenerative process that unfortunately is an inevitable part of life and risk factor for cardiovascular disease including heart failure. Among the several theories purported to explain the effects of age on cardiac dysfunction, the mitochondrion has emerged a central regulator of this process. Hence, it is not surprising that abnormalities in mitochondrial quality control including biogenesis and turnover have such detrimental effects on cardiac function. In fact mitochondria serve as a conduit for biological signals for apoptosis, necrosis and autophagy respectively. The removal of damaged mitochondria by autophagy/mitophagy is essential for mitochondrial quality control and cardiac homeostasis. Defects in mitochondrial dynamism fission/fusion events have been linked to cardiac senescence and heart failure. In this review we discuss the impact of aging on mitochondrial dynamics and senescence on cardiovascular health. This article is part of a Special Issue entitled: CV Aging. © 2015 Elsevier Ltd.

Ganguly R.,St Boniface Hospital Research Center | Ganguly R.,University of Manitoba | Pierce G.N.,St Boniface Hospital Research Center | Pierce G.N.,University of Manitoba
Molecular Nutrition and Food Research | Year: 2012

Coronary heart disease is becoming a worldwide epidemic and diet and lifestyle are well known contributing factors. Identifying the kinds of foods that may have a cardioprotective or cardiotoxic effect and understanding their molecular mechanisms of action has become of increasing importance. Through largely epidemiological evidence, trans fatty acid (TFA) intake has been associated with a variety of cardiovascular complications including atherosclerosis. Traditionally, industrial TFAs (iTFAs) have been associated with these deleterious cardiovascular effects. However, there is a current body of research that suggests that ruminant trans fats (rTFAs) may have a cardioprotective role within the heart. The molecular mechanisms whereby TFAs are delivering their effects are largely unknown. In the following review, we discuss recent in vitro, animal and epidemiological research to better understand the effect of TFAs in the diet on cardiovascular disease, particularly atherosclerosis. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Loading St Boniface Hospital Research Center collaborators
Loading St Boniface Hospital Research Center collaborators