N S Dhalla

St. Boniface Hospital Research, Winnipeg, Manitoba, Canada

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Publications (655)1933.14 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In order to examine the reversibility of heart failure due to myocardial infarction (MI) by β-adrenoceptor blockade, 12 wks infarcted rats were treated with or without metoprolol (50 mg/kg/day) for 8 wks. The depressed left ventricular (LV) systolic pressure, positive and negative rates of changes in pressure development, ejection fraction, fractional shortening and cardiac output, as well as increased LV end-diastolic pressure in 20 wks MI animals were partially reversed by metoprolol. MI-induced decreases in septum (systolic) thickness as well as increase in LV posterior wall thickness and LV internal diameter were partially or fully reversible by metoprolol. Treatment of MI animals with metoprolol partially reversed the elevated levels of plasma norepinephrine and dopamine without affecting the elevated levels of epinephrine. Although sarcoplasmic reticular (SR) Ca(2+) -uptake, as well as protein content for SR Ca(2+) -pump and phospholamban, were reduced in the infarcted hearts; these changes were partially reversible with metoprolol. Depressed myofibrillar Ca(2+) -stimulated ATPase activity, as well as mRNA levels for SR Ca(2+) -pump, phospholamban and α-myosin heavy chain, were unaffected whereas increased mRNA level for β-myosin heavy chain was partially reversed by metoprolol. The results suggest that partial improvement of cardiac performance by β-adrenoceptor blockade at advanced stages of heart failure may be due to partial reversal of changes in SR Ca(2+) -pump function whereas partial to complete reverse cardiac remodeling may be due to partial reduction in the elevated levels of plasma catecholamines. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
    Journal of Cellular Physiology 04/2013; · 4.22 Impact Factor
  • Adriana Adameova, Naranjan S Dhalla
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    ABSTRACT: Although heart disease due to diabetes is mainly associated with complications of the large vessels, microvascular abnormalities are also considered to be involved in altering cardiac structure and function. Three major defects, such as endothelial dysfunction, alteration in the production/release of hormones, and shift in metabolism of smooth muscle cells, have been suggested to produce damage to the small arteries and capillaries (microangiopathy) due to hyperglycemia, and promote the development of diabetic cardiomyopathy. These factors may either act alone or in combination to produce oxidative stress as well as changes in cellular signaling and gene transcription, which in turn cause vasoconstriction and structural remodeling of the coronary vessels. Such alterations in microvasculature produce hypoperfusion of the myocardium and thereby lower the energy status resulting in changes in Ca2+-handling, apoptosis, and decreased cardiac contractile force. This article discusses diabetes-induced mechanisms of microvascular damage leading to cardiac dysfunction that is characterized by myocardial dilatation, cardiac hypertrophy as well as early diastolic and late systolic defects. Metabolic defects and changes in neurohumoral system due to diabetes, which promote disturbances in vascular homeostasis, are highlighted. In addition, increase in the vulnerability of the diabetic heart to the development of heart failure and the signaling pathways integrating nuclear factor κB and protein kinase C in diabetic cardiomyopathy are also described for comparison.
    Heart Failure Reviews 03/2013; · 4.45 Impact Factor
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    ABSTRACT: Diabetic cardiomyopathy is not only associated with heart failure but there also occurs a loss of the positive inotropic effect of different agents. It is now becoming clear that cardiac dysfunction in chronic diabetes is intimately involved with Ca(2+)-handling abnormalities, metabolic defects and impaired sensitivity of myofibrils to Ca(2+) in cardiomyocytes. On the other hand, loss of the inotropic effect in diabetic myocardium is elicited by changes in signal transduction mechanisms involving hormone receptors and depressions in phosphorylation of various membrane proteins. Ca(2+)-handling abnormalities in the diabetic heart occur mainly due to defects in sarcolemmal Na(+)-K(+) ATPase, Na(+)-Ca(2+) exchange, Na(+)-H(+) exchange, Ca(2+)-channels and Ca(2+)-pump activities as well as changes in sarcoplasmic reticular Ca(2+)-uptake and Ca(2+)-release processes; these alterations may lead to the occurrence of intracellular Ca(2+) overload. Metabolic defects due to insulin deficiency or ineffectiveness as well as hormone imbalance in diabetes are primarily associated with a shift in substrate utilization and changes in the oxidation of fatty acids in cardiomyocytes. Mitochondria initially seem to play an adaptive role in serving as a Ca(2+) sink, but the excessive utilization of long-chain fatty acids for a prolonged period results in the generation of oxidative stress and impairment of their function in the diabetic heart. In view of the activation of sympathetic nervous system and renin-angiotensin system as well as platelet aggregation, endothelial dysfunction and generation of oxidative stress in diabetes and blockade of their effects have been shown to attenuate subcellular remodeling, metabolic derangements and signal transduction abnormalities in the diabetic heart. On the basis of these observations, it is suggested that oxidative stress and subcellular remodeling due to hormonal imbalance and metabolic defects play a critical role in the genesis of heart failure during the development of diabetic cardiomyopathy.
    Heart Failure Reviews 02/2013; · 4.45 Impact Factor
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    ABSTRACT: Oxidative stress is considered to play an important role in the pathogenesis of diabetes-induced cardiovascular disease (CVD), which is invariably associated with abnormal blood lipid profile, insulin resistance and metabolic syndrome. Stress, smoking, high saturated fat intake as well as low fruit and vegetable intakes have been shown to increase oxidative stress and hyperlipidemia, which increase the predisposition of diabetic subjects to atherosclerosis, stroke and coronary heart disease. The oxidation of low-density lipoprotein by oxidative stress is essential for the development of atherosclerosis, and the reduction in oxidative stress as well as blood glucose and cholesterol is considered critical for the prevention of diabetes-induced CVD. Although epidemiological studies have demonstrated that vitamin C and vitamin E decrease the incidence of coronary heart disease, different clinical trials have failed to support the beneficial effect of these antioxidants. Nonetheless, it has been suggested that natural forms of these vitamins may be more efficacious than synthetic vitamins, and this may explain the inconsistencies in results. Antioxidants, N-acetyl-L-cysteine and resveratrol, have also been shown to attenuate the diabetes-induced cardiovascular complications. It has been indicated that the antioxidant therapy may be effective in a prevention strategy rather than as a treatment for CVD. The evidence presented here supports the view that cardiovascular complications in diabetes may be induced by oxidative stress and appropriate antioxidant therapy may be promising for attenuating the progression of diabetes-induced CVD.
    Heart Failure Reviews 02/2013; · 4.45 Impact Factor
  • Naranjan S Dhalla, Satoshi Takeda, Vijayan Elimban
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    ABSTRACT: Abstract Although vitamin B6 and its metabolite, pyridoxal 5'-phosphate (PLP), have been shown to exert beneficial effects in ischemic heart disease, the mechanisms of their action are not fully understood. Some studies have shown that ventricular arrhythmias and mortality upon the occlusion of coronary artery were attenuated by pretreatment of animals with PLP. Furthermore, ischemia-reperfusion-induced abnormalities in cardiac performance and defects in sarcoplasmic reticular Ca2+-transport activities were decreased by PLP. The increase in cardiac contractile activity of isolated heart by ATP was reduced by PLP, unlike propranolol, whereas that by isoproterenol was not depressed by PLP. ATP-induced increase in [Ca2+]i, unlike KCl-induced increase in [Ca2+]i in cardiomyocytes was depressed by PLP. Both high- and low-affinity sites for ATP binding in sarcolemmal membranes were also decreased by PLP. These observations support the view that PLP may produce cardioprotective effects in ischemic heart disease by attenuating the occurrence of intracellular Ca2+ overload due to the blockade of purinergic receptors.
    Clinical Chemistry and Laboratory Medicine 01/2013; · 3.01 Impact Factor
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    ABSTRACT: We examined the role of redox-sensitive signal transduction mechanisms in modifying the changes in [Ca(2+)](i) produced by ouabain upon incubating adult rat cardiomyocytes with antioxidants or inhibitors of different protein kinases and monitoring alterations in fura-2 fluorescence. Ouabain increased basal [Ca(2+)](i), augmented the KCl-induced increase in [Ca(2+)](i), and promoted oxyradical production in cardiomyocytes. These actions of ouabain were attenuated by an oxyradical scavenging mixture (superoxide dismutase plus catalase), and the antioxidants (N-acetyl-l-cysteine and N-(2-mercaptoproprionyl)glycine). An inhibitor of MAP kinase (PD98059) depressed the ouabain-induced increase in [Ca(2+)], whereas inhibitors of tyrosine kinase (tyrphostin and genistein) and PI3 kinase (Wortmannin and LV294002) enhanced the ouabain-induced increase in [Ca(2+)](i). Inhibitors of protein kinase C (calphostin and bisindolylmalaimide) augmented the ouabain-induced increase in [Ca(2+)](i), whereas stimulation of protein kinase C by a phorbol ester (phorbol 12-myristate 13-acetate) depressed the action of ouabain. These results suggest that ouabain-induced inhibition of Na (+)-K(+) ATPase may alter the redox status of cardiomyocytes through the production of oxyradicals, and increase the activities of various protein kinases. Thus, these redox-sensitive signal transduction mechanisms involving different protein kinases may modify Ca(2+)-handling sites in cardiomyocytes and determine the magnitude of net increase in [Ca(2+)](i) in response to ouabain.
    Canadian Journal of Physiology and Pharmacology 01/2013; 91(1):45-55. · 1.56 Impact Factor
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    World Heart Journal 01/2013; 6(1).
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    ABSTRACT: This study was undertaken to examine the effects of dietary supplementation of cysteine and taurine in rats with diabetes induced with streptozotocin (STZ, 65 mg/kg body weight). Experimental animals were treated orally (by gavage) with cysteine (200 mg/kg) and taurine (400 mg/kg), alone or in combination, daily for 8 wks. In one group, rats were also pretreated 3 wks before the induction of diabetes (prevention arm) whereas in the other, the treatment was started 3 days after the induction of diabetes (reversal arm). Diabetes increased heart weight/body weight (HW/BW) ratio, plasma glucose, triglyceride and cholesterol levels as well as depressed heart rate (HR), blood pressure, left ventricular systolic pressure (LVSP), rate of contraction (+dP/dt), rate of relaxation (-dP/dt), fractional shortening (FS) and cardiac output (CO). The left ventricular internal diameter in systole (LViDs) was increased whereas that in diastole (LViDd) was decreased. In the prevention arm, treatment of the diabetic animals with cysteine or taurine decreased HW/BW ratio and improved HR, FS, +dP/dt and -dP/dt, as well as normalized LViDs, without altering the increase in glucose level. Cysteine decreased plasma triglyceride and cholesterol levels and improved LVSP whereas CO was improved by taurine. In the reversal arm, cysteine alone or with taurine did not correct the changes in hemodynamic parameters, FS and plasma triglycerides. Diabetes-induced cardiac dysfunction and increases in plasma triglycerides can be prevented, but not reversed, by dietary cysteine alone or in combination with taurine.
    Physiological research / Academia Scientiarum Bohemoslovaca 12/2012; · 1.53 Impact Factor
  • Alison L Müller, Darren Freed, Naranjan S Dhalla
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    ABSTRACT: 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 to 60 min of global ischemia were accompanied by augmented activities of both calpain and matrix metalloproteinases (MMPs) and depressed protein content of β-1 and β-2 subunits, without changes in α-1 and α-2 subunits of the enzyme. In comparison to 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 to 40 min except that α-1 and α-2 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 α-2 subunit than doxycycline, an MMP inhibitor. Incubation of control SL preparation with calpain, unlike MMP-2, depressed Na(+)-K(+) ATPase activity and decreased α-1, α-2 and β-2 subunits without changes in the β-1 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.
    Journal of Applied Physiology 12/2012; · 3.48 Impact Factor
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    ABSTRACT: This study tested the reversal of subcellular remodeling in heart failure due to myocardial infarction (MI) upon treatment with losartan, an angiotensin II receptor antagonist. Twelve wks after inducing MI, rats were treated with or without losartan (20 mg/kg; daily) for 8 wks and assessed for cardiac function, cardiac remodeling, subcellular alterations and plasma catecholamines. Cardiac hypertrophy and lung congestion in 20 wks MI-induced heart failure were associated with increases in plasma catecholamine levels. Hemodynamic examination revealed depressed cardiac function whereas echocardiographic analysis showed impaired cardiac performance and marked increases in left ventricle wall thickness and chamber dilatation at 20 wks of inducing MI. These changes in cardiac function, cardiac remodeling and plasma dopamine levels in heart failure were partially or fully reversed by losartan. Sarcoplasmic reticular (SR) Ca(2+) -pump activity and protein expression, protein and gene expression for phospholamban, as well as myofibrillar (MF) Ca(2+) -stimulated ATPase activity and α-myosin heavy chain mRNA levels were depressed whereas β-myosin heavy chain expression was increased in failing hearts; these alterations were partially reversed by losartan. Although SR Ca(2+) -release activity and mRNA levels for SR Ca(2+) -pump were decreased in failing heart, these changes were not reversed upon losartan treatment; no changes in mRNA levels for SR Ca(2+) -release channels were observed in untreated or treated heart failure. These results suggest that partial improvement of cardiac performance in heart failure due to MI by losartan treatment is associated with partial reversal of cardiac remodeling as well as partial recovery of SR and MF functions. © 2012 The Authors Journal of Cellular and Molecular Medicine © 2012 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.
    Journal of Cellular and Molecular Medicine 09/2012; · 4.75 Impact Factor
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    [Show abstract] [Hide abstract]
    ABSTRACT: Although diabetes due to insulin deficiency or insulin resistance is a major cause of heart disease, the pathogenesis of cardiac dysfunction during the development of diabetic cardiomyopathy is not fully understood. Varying degrees of defects in subcellular organelles, such as sarcolemma, mitochondria, sarcoplasmic reticulum, myofibrils and extracellular matrix have been observed in the diabetic heart. These subcellular abnormalities in chronic diabetes become evident with the occurrence of hormonal imbalance, metabolic defects, oxidative stress and intracellular Ca(2+) overload. During the initial stages of diabetes, hormonal imbalances, including elevated plasma levels of catecholamines and angiotensin II, as well as metabolic defects, appear to favour the development of oxidative stress; these changes lead to subcellular defects in the myocardium. Reductions in sarcoplasmic reticular Ca(2+) pump and Ca(2+) release channel function are associated with cardiac dysfunction, whereas alterations in sarcolemmal Na(+)/Ca(2+) exchanger and Na(+)/K(+) ATPase activities contribute to intracellular Ca(2+) overload at late stages of diabetes. The continued accumulation of Ca(2+) in mitochondria produces Ca(2+) overload in these organelles, and this change induces impairment of energy production and depletion of energy stores as well as further promotion of oxidative stress in chronic diabetes. Generation of oxyradicals due to impaired electron transport results in the opening of mitochondrial pores, leakage of toxic proteins and myocardial cell damage in diabetes. These observations support the view that alterations in sarcoplasmic reticular and mitochondrial functions produce intracellular Ca(2+) overload and depletion of energy stores and, thus, play an important role in the development of cardiac dysfunction in diabetic cardiomyopathy.
    Experimental and clinical cardiology 09/2012; 17(3):115-20. · 1.10 Impact Factor
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    ABSTRACT: It has become evident that protein degradation by proteolytic enzymes, known as proteases, is partly responsible for cardiovascular dysfunction in various types of heart disease. Both extracellular and intracellular alterations in proteolytic activities are invariably seen in heart failure associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, hypertensive cardiomyopathy, diabetic cardiomyopathy, and ischemic cardiomyopathy. Genetic cardiomyopathy displayed in different strains of hamsters provides a useful model for studying heart failure due to either cardiac hypertrophy or cardiac dilation. Alterations in the function of several myocardial organelles such as sarcolemma, sarcoplasmic reticulum, myofibrils, mitochondria, as well as extracellular matrix have been shown to be due to subcellular remodeling as a consequence of changes in gene expression and protein content in failing hearts from cardiomyopathic hamsters. In view of the increased activities of various proteases, including calpains and matrix metalloproteinases in the hearts of genetically determined hamsters, it is proposed that the activation of different proteases may also represent an important determinant of subcellular remodeling and cardiac dysfunction associated with genetic cardiomyopathy.
    Canadian Journal of Physiology and Pharmacology 07/2012; 90(8):995-1004. · 1.56 Impact Factor
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    ABSTRACT: Sarpogrelate (SP), a serotonin (5-HT2A) receptor antagonist, is used as an anti-platelet agent for the treatment of some vascular diseases. SP has been reported to inhibit 5-HT induced coronary artery spasm, increase in intracellular calcium and smooth muscle cells proliferation. This study was undertaken to test that SP suppresses the development of atherosclerosis due to high cholesterol diet (HCD) by decreasing blood viscosity and oxidative stress. For this purpose, 29 rabbits were divided into four groups: control group (normal diet); normal diet group with SP at the dose of 5 mg/kg/day; HCD group fed 1% cholesterol; and HCD group with SP at the dose of 5 mg/kg/day. After 90 days of the experiment, blood samples were collected and the animals were killed; the thoracic aorta was stained by the Oil Red O staining method. The results indicate that plasma levels of cholesterol, triglycerides and malondialdehyde were increased in rabbits fed HCD. Plasma viscosity and whole blood viscosity were also higher in the HCD group than that in normal diet group. Treatment with SP prevented these alterations induced by HCD whereas this agent had no significant effect in rabbits fed normal diet. Morphological examination of the aorta revealed that SP treatment prevented the formation of foam cells and atherosclerotic plaque. It is suggested that the beneficial effects of SP in atherosclerosis may be due to actions on blood viscosity, lipid levels and oxidative stress.
    Journal of Cellular and Molecular Medicine 02/2012; 16(10):2394-400. · 4.75 Impact Factor
  • Alison L Müller, Larry V Hryshko, Naranjan S Dhalla
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    ABSTRACT: Various procedures such as angioplasty, thrombolytic therapy, coronary bypass surgery, and cardiac transplantation are invariably associated with ischemia-reperfusion (I/R) injury. Impaired recovery of cardiac function due to I/R injury is considered to be a consequence of the occurrence of both oxidative stress and intracellular Ca(2+)-overload in the myocardium. These changes in the ischemic myocardium appear to activate both extracellular and intracellular proteases which are responsible for the cleavage of extracellular matrix and subcellular structures involved in the maintenance of cardiac function. It is thus intended to discuss the actions of I/R injury on several proteases, with a focus on calpain, matrix metalloproteinases, and cathepsins as well as their role in inducing alterations both inside and outside the cardiomyocytes. In addition, modifications of subcellular organelles such as myofibrils, sarcoplasmic reticulum and sarcolemma as well as extracellular matrix, and the potential regulatory effects of endogenous inhibitors on protease activities are identified. Both extracellular and intracellular proteolytic activities appear to be imperative in determining the true extent of I/R injury and their inhibition seems to be of critical importance for improving the recovery of cardiac function. Thus, both extracellular and intracellular proteases may serve as potential targets for the development of cardioprotective interventions for reducing damage to the heart and retarding the development of contractile dysfunction caused by I/R injury.
    International journal of cardiology 02/2012; · 6.18 Impact Factor
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    Raja B Singh, Larry Hryshko, Darren Freed, Naranjan S Dhalla
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    ABSTRACT: We tested whether the activation of proteolytic enzymes, calpain, and matrix metalloproteinases (MMPs) during ischemia-reperfusion (I/R) is mediated through oxidative stress. For this purpose, isolated rat hearts were subjected to a 30 min global ischemia followed by a 30 min reperfusion. Cardiac function was monitored and the activities of Na(+)/K(+)-ATPase, Mg(2+)-ATPase, calpain, and MMP were measured. Depression of cardiac function and Na(+)/K(+)-ATPase activity in I/R hearts was associated with increased calpain and MMP activities. These alterations owing to I/R were similar to those observed in hearts perfused with hypoxic medium, H(2)O(2) and xanthine plus xanthine oxidase. The I/R-induced changes were attenuated by ischemic preconditioning as well as by perfusing the hearts with N-acetylcysteine or mercaptopropionylglycine. Inhibition of MMP activity in hearts treated with doxycycline depressed the I/R-induced changes in cardiac function and Na(+)/K(+)-ATPase activity without affecting the calpain activation. On the other hand, inhibition of calpain activity upon treatment with leupeptin or MDL 28170 significantly reduced the MMP activity in addition to attenuating the I/R-induced alterations in cardiac function and Na(+)/K(+)-ATPase activity. These results suggest that the I/R-induced depression in Na(+)/K(+)-ATPase and cardiac function may be a consequence of the increased activities of both calpain and MMP because of oxidative stress in the heart.
    Canadian Journal of Physiology and Pharmacology 02/2012; 90(2):249-60. · 1.56 Impact Factor
  • Melissa R Dent, Paramjit S Tappia, Naranjan S Dhalla
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    ABSTRACT: This study was undertaken to determine gender related changes in different components of β-adrenoceptor (β-AR) system in response to arteriovenous fistula (AV-shunt), which is known to produce heart failure due to volume overload. AV-shunt was induced in male and female rats for 16 weeks by the needle technique; ovariectomized (OVX) rats treated with or without estrogen were also used. Although AV-shunt for 16 weeks produced cardiac hypertrophy in both sexes, male animals showed cardiac dysfunction whereas cardiac performance was maintained in females. Both β(1) -AR and β(2) -AR protein content and mRNA levels were decreased in male and increased in female hearts post-AV-shunt. The basal adenylyl cyclase (AC) activity was lower in the female heart; however, AC protein content and the increase in epinephrine (EPi)-stimulated AC activity were greater in the female AV-shunt group as compared to males. While AC V/VI and β-arrestin 2 mRNA levels were decreased in males, mRNA level for GRK2 was increased in females post-AV-shunt. In contrast to intact females, AV-shunt OVX animals showed depressed cardiac function, decreased β(1) -AR, β(2) -AR, and AC protein content, as well as reduced EPi-stimulated AC activity. Treatment of OVX rats with 17-β estradiol attenuated the AV-shunt induced changes in β-AR and AC protein content as well as cardiac dysfunction. These results reveal that β-AR signal transduction system in response to AV-shunt is downregulated in males and upregulated in females. Furthermore, estrogen appears to play an important role in the upregulation of β-AR mechanisms and the maintenance of cardiac function in AV-shunt females.
    Journal of Cellular Physiology 10/2011; 227(8):3080-7. · 4.22 Impact Factor
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    ABSTRACT: Although several risk factors including hypertension, cardiac hypertrophy, coronary artery disease, and diabetes are known to result in heart failure, elderly subjects are more susceptible to myocardial infarction and more likely to develop heart failure. This article is intended to discuss that cardiac dysfunction in hearts failing due to myocardial infarction and aging is associated with cardiac remodeling and defects in the subcellular organelles such as sarcolemma (SL), sarcoplasmic reticulum (SR), and myofibrils. Despite some differences in the pattern of heart failure due to myocardial infarction and aging with respect to their etiology and sequence of events, evidence has been presented to show that subcellular remodeling plays a critical role in the occurrence of intracellular Ca(2+)-overload and development of cardiac dysfunction in both types of failing heart. In particular, alterations in gene expression for SL and SR proteins induce Ca(2+)-handling abnormalities in cardiomyocytes, whereas those for myofibrillar proteins impair the interaction of Ca(2+) with myofibrils in hearts failing due to myocardial infarction and aging. In addition, different phosphorylation mechanisms, which regulate the activities of Ca(2+)-cycling proteins in SL and SR membranes as well as Ca(2+)-binding proteins in myofibrils, become defective in the failing heart. Accordingly, it is suggested that subcellular remodeling involving defects in Ca(2+)-handling and Ca(2+)-binding proteins as well as their regulatory mechanisms is intimately associated with cardiac remodeling and heart failure due to myocardial infarction and aging.
    Heart Failure Reviews 08/2011; 17(4-5):671-81. · 4.45 Impact Factor
  • Alison L Müller, Naranjan S Dhalla
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    ABSTRACT: It is believed that cardiac remodeling due to geometric and structural changes is a major mechanism 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 system have 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 abnormalities with 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.
    Heart Failure Reviews 07/2011; 17(3):395-409. · 4.45 Impact Factor
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    Melissa R Dent, Paramjit S Tappia, Naranjan S Dhalla
    Apoptosis 07/2011; 16(7):757-8. · 4.07 Impact Factor
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    ABSTRACT: Although β-adrenoceptor (β-AR) blockade is an important mode of therapy for congestive heart failure (CHF), subcellular mechanisms associated with its beneficial effects are not clear. Three weeks after inducing myocardial infarction (MI), rats were treated daily with or without 20 and 75 mg/kg atenolol, a selective β(1) -AR antagonist, or propranolol, a non-selective β-AR antagonist, for 5 weeks. Sham operated rats served as controls. All animals were assessed haemodynamically and echocardiographically and the left ventricle (LV) was processed for the determination of myofibrillar ATPase activity, α- and β-myosin heavy chain (MHC) isoforms and gene expression as well as cardiac troponin I (cTnI) phosphorylation. Both atenolol and propranolol at 20 and 75 mg/kg doses attenuated cardiac hypertrophy and lung congestion in addition to increasing LV ejection fraction and LV systolic pressure as well as decreasing heart rate, LV end-diastolic pressure and LV diameters in the infarcted animals. Treatment of infarcted animals with these agents also attenuated the MI-induced depression in myofibrillar Ca(2+) -stimulated ATPase activity and phosphorylated cTnI protein content. The MI-induced decrease in α-MHC and increase in β-MHC protein content were attenuated by both atenolol and propranolol at low and high doses; however, only high dose of propranolol was effective in mitigating changes in the gene expression for α-MHC and β-MHC. Our results suggest that improvement of cardiac function by β-AR blockade in CHF may be associated with attenuation of myofibrillar remodelling.
    Journal of Cellular and Molecular Medicine 03/2011; 15(3):545-54. · 4.75 Impact Factor

Publication Stats

8k Citations
1,933.14 Total Impact Points

Institutions

  • 1987–2013
    • St. Boniface Hospital Research
      • Institute of Cardiovascular Sciences
      Winnipeg, Manitoba, Canada
  • 1970–2013
    • University of Manitoba
      • • Department of Physiology
      • • Faculty of Medicine
      Winnipeg, Manitoba, Canada
  • 2009
    • Texas A&M University System Health Science Center
      Bryan, Texas, United States
  • 2007
    • Jackson Memorial Hospital
      Miami, Florida, United States
    • Texas Tech University Health Sciences Center
      • Department of Pharmaceutical Sciences
      Lubbock, TX, United States
  • 1978–2006
    • The University of Winnipeg
      Winnipeg, Manitoba, Canada
  • 2005
    • Ankara University
      • Department of Biophysics
      Ankara, Ankara, Turkey
  • 2000
    • Tokyo University of Pharmacy and Life Science
      • Department of Molecular and Cellular Pharmacology
      Edo, Tōkyō, Japan
  • 1995–2000
    • Università degli Studi di Perugia
      • Faculty of Medicine
      Perugia, Umbria, Italy
    • Slovak Academy of Sciences
      • Institute for Heart Research
      Presburg, Bratislavský, Slovakia
  • 1999
    • Academy of Sciences of the Czech Republic
      • Fyziologický ústav
      Praha, Hlavni mesto Praha, Czech Republic
  • 1996
    • The Jikei University School of Medicine
      • Department of Internal Medicine
      Tokyo, Tokyo-to, Japan
  • 1994
    • University of Tuebingen
      • Institute for Physiology
      Tübingen, Baden-Wuerttemberg, Germany
  • 1991
    • University of Tartu
      Dorpat, Tartu County, Estonia
  • 1975–1988
    • Hôpital St-Boniface Hospital
      Winnipeg, Manitoba, Canada
  • 1972
    • Washington University in St. Louis
      San Luis, Missouri, United States