Joseph Fomusi Ndisang

University of Saskatchewan, Saskatoon, Saskatchewan, Canada

Are you Joseph Fomusi Ndisang?

Claim your profile

Publications (59)191.28 Total impact

  • Joseph Fomusi Ndisang, Rajni Chibbar
    [Show abstract] [Hide abstract]
    ABSTRACT: Although heme-oxygenase (HO) is cytoprotective, its effects on podocyte regulators like podocalyxin, podocin, CD2-associated protein (CD2AP) in renal dysfunction in N (ω)-nitro-l-arginine-methyl ester (l-NAME) hypertension are largely unclear. Hypertension was induced in normotensive Sprague Dawley rats by administering l-NAME for 4 weeks. Enzyme immunoassay, enzyme-linked immunosorbent, histology/morphology, spectrophotometry, and western immunoblotting were used. HO was enhanced with heme-arginate (HA) or inhibited with chromium mesoporphyrin (CrMP). Treatment with heme-arginate reduced several renal histo-pathological lesions including renal arteriolar thickening, glomerular abnormalities, tubular cast, tubular atrophy/fibrosis, and mononuclear cell infiltration in l-NAME-hypertensive rats. Similarly, HA abated the elevated levels of renal extracellular matrix/profibrotic proteins like collagen and fibronectin that deplete nephrin, a fundamental transmembrane protein that forms the scaffoldings of the podocyte slit diaphragm permitting small ions to filter, but not massive excretion of proteins, hence proteinuria. Correspondingly, HA enhanced the aberrant expression of nephrin alongside other important regulators of podocyte like podocalyxin, podocin, and CD2AP, and improved renal function by reducing albuminuria/proteinuria, while increasing creatinine clearance. The renoprotection by HA were accompanied by significant reduction of inflammatory/oxidative mediators including nuclear factor-kappaB, macrophage inflammatory protein-1-alpha, macrophage chemoattractant protein-1, tumor necrosis factor-alpha, interleukin (IL)-6, IL1β, 8-isoprostane, endothelin-1, and aldosterone. These were associated with increased levels of adiponectin, HO-1, HO activity, cyclic guanosine monophosphate, and atrial natriuretic peptide (ANP), whereas the HO inhibitor, CrMP annulled the renoprotection and exacerbated renal dysfunction. HA improves renal function by attenuating histopathological lesions, suppressing inflammatory/oxidative mediators, abating profibrotic/extracellular matrix proteins, and reducing albuminuria/proteinuria, while concomitantly potentiating the HO-adiponectin-ANP axis, enhancing nephrin, podocin, podocalyxin, CD2AP and increasing creatinine clearance. Our study underscores the benefit of potentiating the HO-adiponectin-ANP against nephropathy. © American Journal of Hypertension, Ltd 2014. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
    American journal of hypertension. 12/2014;
  • Source
    Joseph Fomusi Ndisang, Shuchita Tiwari
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity and excessive inflammation/oxidative stress are pathophysiological forces associated with kidney dysfunction. Although we recently showed that heme-oxygenase (HO) improves renal functions, the mechanisms are largely unclear. Moreover, the effects of the HO-system on podocyte cytoskeletal proteins like podocin, podocalyxin, CD2-associated-protein (CD2AP) and proteins of regeneration/repair like beta-catenin, Oct3/4, WT1 and Pax2 in renal tissue from normoglycemic obese Zucker-fatty rats (ZFs) have not been reported. Treatment with hemin reduced renal histo-pathological lesions including glomerular-hypertrophy, tubular-cast, tubular-atrophy and mononuclear cell-infiltration in ZFs. These were associated with enhanced expression of beta-catenin, Oct3/4, WT1, Pax2 and nephrin, an essential transmembrane protein required for the formation of the scaffoldings of the podocyte slit-diaphragm, permitting the filtration of small ions, but not massive excretion of proteins, hence proteinuria. Besides nephrin, hemin also enhanced other important podocyte-regulators including, podocalyxin, podocin and CD2AP. Correspondingly, albuminuria and proteinuria were reduced, while creatinine clearance increased, suggesting improved renal function in hemin-treated ZFs. The renoprotection by hemin was accompanied by the reduction of inflammatory/oxidative mediators including, macrophage-inflammatory-protein-1α, macrophage-chemoattractant-protein-1 and 8-isoprostane, whereas HO-1, HO-activity and the total-anti-oxidant-capacity increased. Contrarily, the HO-inhibitor, stannous-mesoporphyrin nullified the reno-protection by hemin. Collectively, these data suggest that hemin ameliorates nephropathy by potentiating the expression of proteins of repair/regeneration, abating oxidative/inflammatory mediators, reducing renal histo-pathological lesions, while enhancing nephrin, podocin, podocalyxin, CD2AP and creatinine clearance, with corresponding reduction of albuminuria/proteinuria suggesting improved renal function in hemin-treated ZFs. Importantly, the concomitant potentiation regeneration proteins and podocyte cytoskeletal proteins are novel mechanisms by which hemin rescue nephropathy in obesity. Highlights •Renal dysfunction is common in obesity.•Novel mechanisms by which heme-oxygenase (HO) rescue kidney failure are unveiled.•HO enhance podocyte cytoskeletal proteins like podocin, podocalyxin and CD2AP.•HO enhance proteins of regeneration/repair like beta-catenin, Oct3/4, WT1 and Pax2.
    Redox Biology. 09/2014;
  • Joseph Fomusi Ndisang, Shuchita Tiwari
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress and inflammation are implicated in tissue remodeling, hypertrophy, and organ malfunction. Since heme-oxygenase (HO) is a cytoprotective enzyme with effects against oxidative stress and inflammation, we investigated the effects of upregulating HO with hemin on adipocyte hypertrophy, proteins of repair/regeneration including beta-catenin, Oct3/4 and Pax2 as well as pro-fibrotic/remodeling proteins like osteopontin and transforming growth factor-beta (TGF-β) in pericardial adipose tissue from obese Zucker rats (ZRs). Treatment with hemin significantly reduced pericardial adipose tissue inflammation/oxidative stress, suppressed osteopontin and TGF-β, and attenuated pericardial adipocyte hypertrophy in obese ZRs. These were associated with enhanced expression of the stem/progenitor-cell marker cKit; the potentiation of several proteins of regeneration including beta-catenin, Oct3/4, Pax2; and improved pericardial adipocyte morphology. Interestingly, the amelioration of adipocyte hypertrophy in hemin-treated animals was accompanied by improved adipocyte function, evidenced by increased levels of pericardial adipose tissue adiponectin. Furthermore, hemin significantly reduced hypertriglyceridemia and hypercholesteromia in obese ZRs. The protective effects of hemin were accompanied by robust potentiation HO activity and the total antioxidant capacity, whereas the co-administration of hemin with the HO inhibitor, stannous mesoporphyrin abolished the effects of hemin. These data suggest that hemin improves pericardial adipocyte morphology and function by enhancing proteins of repair and regeneration, while concomitantly abating inflammatory/oxidative insults and suppressing extracellular-matrix/profibrotic and remodeling proteins. The reduction of hypertriglyceridemia, hypercholesteromia, pericardial adiposity, and pericardial adipocyte hypertrophy with corresponding improvement of adipocyte morphology/function in hemin-treated animals suggests that HO inducers may be explored for the design of novel remedies against cardiac complications arising from excessive adiposity.
    Experimental biology and medicine (Maywood, N.J.). 07/2014;
  • Joseph Fomusi Ndisang, Rajni Chibbar, Nina Lane
    [Show abstract] [Hide abstract]
    ABSTRACT: Heart failure and related cardiac complications remains a great health challenge. We investigated the effects of upregulating heme-oxygenase (HO) on myocardial histo-pathological lesions, proinflammatory cytokines/chemokines, oxidative mediators and important markers of heart failure such as osteopontin and osteoprotergerin in N(ω)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Treatment with the HO-inducer, heme-arginate improved myocardial morphology in L-NAME hypertensive rats by attenuating subendocardial injury, interstitial fibrosis, mononuclear-cell infiltration and cardiomyocyte hypertrophy. These were associated with the reduction of several inflammatory/oxidative mediators including chemokines/cytokines such as macrophage inflammatory protein-1 alpha (MIP-1α), macrophage chemoattractant protein-1 (MCP-1), tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1β, endothelin-1, 8-isoprostane, nitrotyrosine, and aldosterone. Similarly, heme-arginate abated the elevated levels of extracellular matrix/remodeling proteins including transforming-growth factor beta (TGF-β1) and collagen-IV in the myocardium. These were accompanied by significant reduction of proteins of heart failure such as osteopontin and osteoprotegerin. Interestingly, the cardio-protective effects of heme-arginate were associated with the potentiation of adiponectin, atrial-natriuretic peptide (ANP), HO-1, HO-activity, cyclic gnanosine monophosphate (cGMP) and the total-anti-oxidant capacity, whereas the HO-inhibitor, chromium-mesoporphyrin nullified the effects of heme-arginate, exacerbating inflammatory injury and oxidative insults. We conclude that heme-arginate therapy protects myocardial damage by potentiating the HO-adiponectin-ANP axis, which in turn suppressed the elevated levels of aldosterone, pro-inflammatory chemokines/cytokines, mononuclear-cell infiltration and oxidative stress, with concomitant reduction of extracellular matrix/remodeling proteins and heart failure proteins. These data suggest a cardio-protective role of the HO system against L-NAME-induced hypertension that could be explored in the design of novel strategies against cardiomyopathy.
    European journal of pharmacology 04/2014; · 2.59 Impact Factor
  • Source
    Joseph Fomusi Ndisang, Ashok Jadhav, Manish Mishra
    [Show abstract] [Hide abstract]
    ABSTRACT: The growing incidence of chronic kidney disease remains a global health problem. Obesity is a major risk factor for type-2 diabetes and renal impairment. Perirenal adiposity, by virtue of its anatomical proximity to the kidneys may cause kidney disease through paracrine mechanisms that include increased production of inflammatory cytokines. Although heme-oxygenase (HO) is cytoprotective, its effects on perirenal adiposity and diabetic nephropathy in Zucker-diabetic fatty rats (ZDFs) remains largely unclear. Upregulating the HO-system with hemin normalised glycemia, reduced perirenal adiposity and suppressed several pro-inflammatory/oxidative mediators in perirenal fat including macrophage-inflammatory-protein-1α (MIP-1α), endothelin (ET-1), 8-isoprostane, TNF-α, IL-6 and IL-1β. Furthermore, hemin reduced ED1, a marker of pro-inflammatory macrophage-M1-phenotype, but interestingly, enhanced markers associated with anti-inflammatory M2-phenotype such as ED2, CD206 and IL-10, suggesting that hemin selectively modulates macrophage polarization towards the anti-inflammatory M2-phenotype. These effects were accompanied by increased adiponectin, HO-1, HO-activity, atrial-natriuretic peptide (ANP), and its surrogate marker, urinary-cGMP. Furthermore, hemin reduced renal histological lesions and abated pro-fibrotic/extracellular-matrix proteins like collagen and fibronectin that deplete nephrin, an important transmembrane protein which forms the scaffolding of the podocyte slit-diaphragm allowing ions to filter but not massive excretion of proteins, hence proteinuria. Correspondingly, hemin increased nephrin expression in ZDFs, reduced markers of renal damage including, albuminuria/proteinuria, but increased creatinine-clearance, suggesting improved renal function. Conversely, the HO-blocker, stannous-mesoporphyrin nullified the hemin effects, aggravating glucose metabolism, and exacerbating renal injury and function. The hemin effects were less-pronounced in Zucker-lean controls with healthy status, suggesting greater selectivity of HO in ZDFs with disease. We conclude that the concomitant reduction of pro-inflammatory/oxidative mediators, macrophage infiltration and profibrotic/extracellular-matrix proteins, coupled to increased nephrin, adiponectin, ANP, cGMP and creatinine clearance may account for improved renal function in hemin-treated ZDFs. These findings suggest that HO-inducers like hemin may be explored against the co-morbidity of perirenal adiposity and diabetic nephropathy.
    PLoS ONE 01/2014; 9(1):e87936. · 3.53 Impact Factor
  • Source
    Joseph Fomusi Ndisang, Sharad Rastogi, Alfredo Vannacci
    Journal of Diabetes Research 01/2014; 2014:276475. · 3.54 Impact Factor
  • Source
    Joseph Fomusi Ndisang, Alfredo Vannacci, Sharad Rastogi
    Oxidative Medicine and Cellular Longevity 01/2014; 2014:506948.
  • Joseph Fomusi Ndisang
    [Show abstract] [Hide abstract]
    ABSTRACT: Peroxisome-proliferator-activated-receptors (PPARs) are transcription factors belonging to the superfamily of nuclear receptors. The isoforms of PPAR include PPAR alpha, PPAR gamma and PPAR delta (also known as PPAR beta). Generally, PPARs potentiate insulin sensitivity, improve glucose/lipid metabolism, suppress inflammation/oxidative stress, attenuate excessive immune responses, regulate cell-growth and differentiation. Interestingly, agonists of PPAR gamma and PPAR alpha have been shown to upregulate the heme-oxygenase (HO)-system. Conversely, the HO-system also enhances PPAR alpha, and potentiates the expression and activity of PPAR gamma. Moreover, the HO-system and related products including bilirubin, biliverdin, carbon monoxide and ferritin have been shown to increase insulin sensitivity, improve glucose/lipid metabolism, suppress inflammation/oxidative stress, abate immune response, and modulate cell-growth/differentiation. Therefore, an intimate, reciprocal, stimulatory and synergistic relationship between PPAR-signaling and the HO-system can be envisaged in the regulation of physiological functions. Thus, both the HO-system and PPARs-signaling participate in fine-tuning similar physiological functions, so novel pharmacological agents capable of optimizing this interaction should be sought. The coordinated regulation of PPAR-signaling and the HO-system may constitute the basis for future drug design.
    Frontiers in Bioscience 01/2014; 19:916-935. · 3.29 Impact Factor
  • Source
    Joseph Fomusi Ndisang, Sharad Rastogi, Alfredo Vannacci
    Research Journal of Immunology 01/2014; 2014:579560.
  • Joseph Fomusi Ndisang, Ashok Jadhav
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetic nephropathy is characterized by elevated macrophage infiltration and inflammation. Although heme-oxygenase (HO) is cytoprotective, its role in macrophage infiltration and nephropathy in type-1 diabetes is not completely elucidated.Administering the HO-inducer, hemin to streptozotocin (STZ)-diabetic rats suppressed renal pro-inflammatory macrophage-M1-phenotype alongside several pro-inflammatory agents, chemokines and cytokines including macrophage-inflammatory-protein-1-alpha (MIP-1α), macrophage-chemoattractant-protein-1 (MCP-1), TNF-α, IL-1β, IL-6, NF-κB and aldosterone, a stimulator of the inflammatory/oxidative transcription factor, NF-κB. Similarly, hemin therapy attenuated extracellular-matrix/profibrotic proteins implicated in renal injury including fibronectin, collagen-IV and TGF-β1, and reduced several renal histo-pathological lesions such as glomerulosclerosis, tubular-necrosis, tubular-vacuolization and interstitial macrophage infiltration. Furthermore, hemin reduced markers of kidney dysfunction like proteinuria and albuminuria, but increased creatinine clearance, suggesting improved kidney function. Correspondingly, hemin significantly enhanced the anti-inflammatory macrophage-M2-phenotype, IL-10, adiponectin, HO-1, HO-activity and atrial-natriuretic-peptide (ANP), a substance that abates TNF-α, IL-6 and IL1β, with parallel increase of urinary-cGMP, a surrogate marker of ANP. Contrarily, co-administering the HO-inhibitor, chromium-mesoporphyrin (CrMP) with the HO-inducer, hemin nullified the anti-diabetic and renoprotective effects, whereas administering CrMP alone abrogated basal HO-activity, reduced basal adiponectin and ANP levels, aggravated hyperglycemia and further increased MCP-1, MIP-1α, aldosterone, NF-κB, TNF-α, IL-6, IL1β, proteinuria/albuminuria and aggravated creatinine clearance, thus exacerbated renal dysfunction, suggesting the importance of the basal HO-adiponectin-ANP axis in renoprotection and kidney function.Collectively, these data suggest that hemin ameliorates diabetic nephropathy by selectively enhancing the anti-inflammatory macrophage-M2-phenotype and IL-10, while concomitantly abating the pro-inflammatory macrophage-M1-phenotype and suppressing extracellular-matrix/profibrotic factors with reduction of renal lesions including interstitial macrophage infiltration. Since aldosterone stimulate NF-κB which activates cytokines like TNF-α, IL-6, IL-1β which in turn stimulate chemokines such as MCP-1 and MIP-1α to promote macrophage-M1-infiltration, the hemin-dependent potentiation of the HO-adiponectin-ANP axis may account for reduced macrophage infiltration and inflammatory insults in STZ-diabetic rats.
    Endocrinology 10/2013; · 4.72 Impact Factor
  • Shuchita Tiwari, Joseph Fomusi Ndisang
    [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes is a complex endocrine/metabolic disease with many related complications including micro-vascular and macro-vascular problems such as cardiomyopathy, nephropathy, neuropathy and retinopathy. Generally, type-1 diabetes is caused by autoimmune-mediated destruction of pancreatic beta cells leading to insulin deficiency. This is usually accompanied by dyslipidemia, enhanced hyperglycemia-mediated oxidative stress, endothelial-cell dysfunction and apoptosis. For decades, type-1 diabetes has been traditionally known as insulin-dependent, while type-2 as non-insulin dependent diabetes. However, it is becoming increasingly clear that insulin deficiency and insulin resistance are manifested in both forms of diabetes at different stages. Thus, it may be time revisit the nomenclature and adjust it to reflect these observations of insulin deficiency and insulin resistance in both forms of diabetes to avoid ambiguity when discussing forms of diabetes. Emerging evidence indicates that the heme-oxygenase (HO) system and related products including carbon monoxide, ferritin and biliverdin are capable of suppressing immune/inflammatory response, and abate oxidative stress and apoptosis. More importantly, upregulating the HO-system increases pancreatic beta-cell insulin release and reduce hyperglycemia in different diabetic models. Similarly, carbon monoxide, a product of the HO-catalyzed degradation of heme also enhances insulin production and improves glucose metabolism. Since excessive immune/inflammatory responses coupled to elevated apoptosis are among the cardinal pathophysiological features type-1 diabetes, this review highlights the role of the HO system and related products such as carbon monoxide and bilirubin in the modulation of apoptosis and immune response, and the beneficial effects of the HO-system in the pathogenesis of type-1 diabetes and related cardiometabolic complications.
    Current pharmaceutical design 07/2013; · 4.41 Impact Factor
  • Joseph Fomusi Ndisang
    [Show abstract] [Hide abstract]
    ABSTRACT: Although recent studies have underscored the role of the heme-oxygenase (HO) inducer hemin, on insulin-signaling and glucose metabolism, the underlying mechanisms are not completely understood. In this study, two-dimensional-gel electrophoresis, mass-spectrometry and MSACOT-analyses were used to identify and characterize novel proteins modulated by hemin in spontaneous-hypertensive rat (SHR), a model of essential hypertension with insulin resistance/impaired glucose metabolism. In addition, the effects of hemin on endothelin-1 (ET-1), protein-tyrosine-phosphatase-1B (PTP-1B), atrial-natriuretic-peptide (ANP) and its surrogate-marker urinary cGMP, and inflammatory cytokines including TNF-IL-6 and IL-1 was investigated. In hemin-treated SHR, several proteins related to oxidative-stress and metabolism were modulated. Particularly, hemin enhanced aldolase-B, fumarylacetoacetate hydrolase, purine-nucleoside phosphorylase, adenosine-kinase, argininosuccinate synthetase and carbonic anhydrase-3 all of which are enzymes involved in glucose/energy metabolism and pH homeostasis. Similarly, hemin potentiated anti-oxidant pathways including, NADP(+)-dependant isocitrate-dehydrogenase, catalase, glutathione-S-transferase-Yb1 and hsp70, a pleiotropic agent that regulates protein-folding, oxidative/pro-inflammatory events. Hemin also increased enzymes implicated in cell-growth such as the nitrilase-protein-family, but reduced betaine-homocysteine methyltransferase, an enzyme associated with insulin resistance and dysfunctional glucose metabolism. Furthermore, hemin increased ANP and its surrogate marker, urinary cGMP, but reduced ET-1, PTP-1B, TNF-IL-6, IL-1β, whereas the HO-inhibitor, chromium-mesoporphyrin abolished the effects. The potentiation of ANP, urinary-cGMP, aldolade-B, fumarylacetoacetate hydrolase, purine-nucleoside phosphorylase, adenosine-kinase, argininosuccinate synthetase, carbonic anhydrase-3, hsp70 and the corresponding reduction of betaine-homocysteine methyltransferase, PTP-1B, TNF-IL-6, IL-1β, and ET-1 may be responsible for the improved glucose metabolism in hemin-treated animals. Collectively, these findings underscore the pleiotropic effects of the HO-system in cellular homeostasis with important roles in metabolism and defence.
    Current pharmaceutical design 07/2013; · 4.41 Impact Factor
  • Shuchita Tiwari, Joseph Fomusi Ndisang
    [Show abstract] [Hide abstract]
    ABSTRACT: Hypertension is a complex interplay of interrelated etiologies, and the leading risk factor for many cardiovascular morbidity and mortality worldwide. Some cardinal pathophysiological features of hypertension include enhanced vascular inflammation, vascular remodeling, vascular contractility and increased oxidative stress. It has been postulated that an imbalance between amount of antioxidants and reactive oxygen species (ROS) results in high blood pressure that eventually leads to the development of hypertension. In response to such oxidative insult, many physiological pathways like the heme oxygenase (HO) system is elicited. The HO system exhibits cytoprotective role and participates in the modulation of cellular homeostasis. Importantly, the HO system plays a vital role in a wide spectrum of physiologic including the regulation of blood vessel tone, and alterations in the activity and expression of HO has been correlated to pathophysiology of hypertension and related complications such as hypertrophy, myocardial infarction and heart failure. Moreover, the cytoprotection exerted by HO is attributable to its catabolic products namely, carbon monoxide, bilirubin/biliverdin, and ferritin that are known to modulate immune, inflammatory and oxidative insults.
    Current pharmaceutical design 07/2013; · 4.41 Impact Factor
  • Manish Mishra, Joseph Fomusi Ndisang
    [Show abstract] [Hide abstract]
    ABSTRACT: The increased prevalence of diabetes and associated complications presents a major health risk worldwide, and requires an efficient management protocol. Type-1 and type-2 diabetes have several common pathophysiological denominators including hyperglycemia, elevated oxidative stress, increased inflammation and apoptosis. These pathological factors are implicated in the progression and worsening of the disease, and the related cardiometabolic complications associate with it. Despite the advancement in management of type-1 and type-2 diabetes, the high incidence of diabetes and related complications calls for novel therapeutic strategies. Recent findings suggest that the pharmacological modulation of the microsomal heme oxygenase (HO) system may be an important therapeutic avenue to explore. The HO system and related products such as carbon monoxide, bilirubin, biliverdin, biliverdin reductase and ferritin have been shown to abate inflammation, oxidative stress, and apoptosis and reduce hyperglycemia. In addition, the HO system also enhances insulin sensitivity and increase pancreatic beta cell insulin production in experimental models of type-1 and type-2 diabetes. This review is an effort to provide evidence of the regulatory and cytoprotective role of the HO system in type-1 and type-2 diabetes, and will highlight the multifaceted mechanisms implicated in the anti-diabetic effects of the HO system.
    Current pharmaceutical design 07/2013; · 4.41 Impact Factor
  • Shuchita Tiwari, Joseph Fomusi Ndisang
    [Show abstract] [Hide abstract]
    ABSTRACT: The growing incidence of obesity and related complications such as cardiomyopathy and nephropathy remains a global health challenge. Many pathophysiological factors including inflammation, oxidative stress and endothelial dysfunction are implicated in obesity-induced abnormalities in the heart and kidney. Moreover, obesity and nutrient-overload are associated with the activation of different inflammatory/oxidative signaling pathways such as endoplasmic reticulum stress, nuclear factor-kappaB (NF-B), toll-like-receptor-4 (TLR4) and the renin-angiotensin-aldosterone system (RAAS). The pathophysiological role of RAAS, TLR4 and NF-B in perturbing physiological milieu is well acknowledged. Several pharmacological agents have been formulated to target one or more of these pathways. Although significant strides have been made in elucidating mechanisms implicated in obesity-related cardio-renal diseases, much still has to be done. The pathophysiology of cardiomyopathy and nephropathy is complex and multifaceted. Besides NF-B, TLR4, RAAS and inflammatory mediators such as cytokines and chemokines, a wide spectrum of different factors including, the environment, diets, lifestyles, genetics and epigenetics are also involved. With such multifactorial etiology, it remains a daunting challenge to identify the factor(s) that initiate the activation and propagation of adverse stimuli that eventually lead to cardiomyopathy and/or nephropathy in obese individuals. Similarly, the mechanisms of such activation and propagation should be clearly elucidated. Should these hurdles be overcome, there would be a greater likelihood for the development of more-effective therapeutic strategies for the prevention, treatment and management of obesity-induced cardiomyopathy and nephropathy. The present review examines the current state of knowledge and future directions of research in the area of obesity-related cardiomyopathy and nephropathy.
    Current pharmaceutical design 07/2013; · 4.41 Impact Factor
  • Joseph Fomusi Ndisang
    Current pharmaceutical design 07/2013; · 4.41 Impact Factor
  • Joseph Fomusi Ndisang, Manish Mishra
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The mechanisms by which heme oxygenase (HO) improves glucose metabolism in essential hypertension are not completely understood. Because dysfunctional insulin signaling is associated with elevated inflammation and high cholesterol and triglycerides, we investigated the effects of HO on the proinflammatory macrophage M1 phenotype and the anti-inflammatory macrophage M2 phenotype in spontaneously hypertensive rats (SHRs). SHRs are a model of human essential hypertension with features of metabolic syndrome, including impaired glucose metabolism. METHODS: Spectrophotometric analysis, enzyme immunoassay, enzyme-linked immunosorbent assay, and Western immunoblotting were used. HO was enhanced with hemin or inhibited with chromium-mesoporphyrin (CrMP). RESULTS: Hemin suppressed inflammation by abating proinflammatory macro phage M1 phenotype (ED1) and chemokines such as macrophage chemoattractant protein 1 (MCP-1) and macrophage inflammatory protein 1 alpha (MIP-1α) while enhancing anti-inflammatory macrophage M2 phenotype by potentiating ED2, CD206, and CD14. Similarly, hemin improved insulin signaling by enhancing insulin receptor substrate 1 (IRS-1), IRS-2, phosphatidylinositol 3 kinase (PI3K), and glucose transporter 4 (GLUT4) but reduced total cholesterol and triglycerides. These effects were accompanied by increased HO-1, HO activity, and cyclic guanosine monophosphate (cGMP), whereas the HO inhibitor CrMP nullified the hemin effects. Importantly, the effects of the HO system on ED1, ED2, CD206, and CD14 in SHRs are novel. CONCLUSIONS: Hemin abated inflammation in SHRs by selectively enhancing the anti-inflammatory macrophage M2 phenotype that dampens inflammation while suppressing the pronflammatory macrophage M1 phenotype and related chemokines such as MCP-1 and MIP-1α. Importantly, the reduction of inflammation, total cholesterol, and triglycerides was accompanied by the enhancement of important proteins implicated in insulin signaling, including IRS-1, IRS-2, PI3K, and GLUT4. Thus, the concomitant reduction of inflammation, total cholesterol and triglycerides and the corresponding potentiation of insulin signaling are among the multifaceted mechanisms by which the HO system improves glucose metabolism in essential hypertension.
    American Journal of Hypertension 06/2013; · 3.67 Impact Factor
  • Joseph Fomusi Ndisang, Ashok Jadhav
    [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: Visceral adiposity and impaired glucose metabolism are common patho-physiological features in patients co-morbid with obesity and type-2 diabetes. We investigated the effects of the heme-oxygenase (HO) inducer, hemin and the HO-blocker, stannous-mesoporphyrin (SnMP) on glucose metabolism, adipocyte hypertrophy, pro-inflammatory cytokines/mediators in Zucker-diabetic-fatty rats (ZDF), a model characterized by obesity and type-2 diabetes. METHODS: Histological, morphological/morphometrical, Western immunoblotting, enzyme immunoassay, ELISA and spectrophotometric analysis were used. RESULTS: Treatment with hemin enhanced HO-1, HO-activity, cGMP, but suppressed retroperitoneal adiposity and abated the elevated levels of macrophage-chemoattractant-protein-1 (MCP-1), ICAM-1, TNF-α, IL-6, IL-1β, NF-κB, c-Jun-NH2-terminal-kinase (JNK) and activating-protein (AP-1), with parallel reduction of adipocyte hypertrophy. Correspondingly, important proteins of lipid metabolism and insulin-signaling such as lipoprotein lipase (LPL), insulin-receptor substrate-1 (IRS-1), GLUT4, PKB/Akt, adiponectin, the insulin-sensitizing and anti-inflammatory protein, and adenosine-monophosphate-activated protein-kinase (AMPK) were significantly enhanced in hemin-treated ZDF. CONCLUSION: Elevated retroperitoneal adiposity and the high levels of MCP-1, ICAM-1, TNF-α, IL-6, IL-1β, NF-κB, JNK and AP-1 in untreated ZDF are patho-physiological factors that exacerbate inflammatory insults, aggravate adipocyte hypertrophy, with corresponding reduction of adiponectin and deregulation of insulin-signaling and lipid metabolism. Therefore, the suppression of MCP-1, ICAM-1, TNF-α, IL-6, IL-1β, NF-κB, JNK, AP-1 and adipocyte hypertrophy, with the associated enhancement of LPL, adiponectin, AMPK, IRS-1, GLUT4, PKB/Akt and cGMP in hemin-treated ZDF are among the multifaceted mechanisms by which the HO-system combat inflammation to potentiate insulin-signaling and improve glucose and lipid metabolism. Thus, HO-inducers may be explored in the search of novel remedies against the co-morbidities of obesity, dysfunctional lipid metabolism and impaired glucose metabolism.
    Diabetes Obesity and Metabolism 06/2013; · 5.18 Impact Factor
  • Ashok Jadhav, Shuchita Tiwari, Paul Lee, Joseph Fomusi Ndisang
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiac function is adversely affected by pericardial adiposity. We investigated the effects of the heme-oxygenase (HO) inducer, hemin on pericardial adiposity, macrophage polarization and diabetic-cardiopathy in Zucker-diabetic-fatty rats (ZDF). Echocardiographic, quantitative-RT-PCR, Western-blot, EIA and spectrophotometric analysis were used. In ZDF-rats, hemin administration increased HO-activity, normalised glycemia, potentiated insulin-signalling by enhancing insulin-receptor-substrate-1 (IRS-1), phosphatidylinositol-3-kinase (PI3K) and protein-kinase-B (PKB), suppressed pericardial-adiposity, cardiac-hypertrophy and left-ventricular longitudinal muscle-fiber-thickness, a pathophysiological feature of cardiomyocyte hypertrophy and correspondingly reduced systolic-blood-pressure and total-peripheral-resistance. In addition, hemin suppressed several pro-inflammatory/oxidative mediators including, NF-κB, c-Jun-N-terminal-kinase (cJNK), endothelin (ET-1), TNF-α, interleukin (IL)-6, IL-1β, activating-protein (AP-1) and 8-isoprostane, whereas the HO-blocker, stannous-mesoporphyrin (SnMP) nullified the hemin-effects. Furthermore, hemin reduced the pro-inflammatory macrophage-M1-phenotype, but enhanced macrophage-M2-phenotype that dampens inflammation. Interestingly, the hemin-effects were less-pronounced in healthy Zucker-lean-rats, suggesting greater selectivity of HO in unhealthy ZDF-rats. Since NF-κB activates TNF-α, IL6 and IL-1β, while TNF-α, JNK and AP-1 impair insulin-signalling, the high levels of these cytokines in obesity/diabetes would create a vicious cycle that together with 8-isoprostane and ET-1 exacerbates cardiac injury, compromising cardiac function. Therefore, the concomitant reduction of pro-inflammatory cytokines and macrophage infiltration coupled to increased expression of IRS-1, PI3K, PKB may account for enhanced glucose metabolism and amelioration of cardiac injury and function in diabetic cardiomyopathy. The hemin-induced preferential polarization of macrophages towards anti-inflammatory M2-phenotype in cardiac tissue and suppression of pericardial adiposity in ZDF-rats are novel findings. Collectively, our study unveils the beneficial effects of hemin on pericardial-adiposity, impaired insulin-signalling and diabetic-cardiomyopathy, and suggests that the multifaceted mechanisms include the suppression of inflammatory/oxidative mediators.
    Journal of Pharmacology and Experimental Therapeutics 02/2013; · 3.89 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The prevalence of non-alcoholic fatty-liver disease (NAFLD) is increasing globally. NAFLD is a spectrum of related liver diseases that progressive from simple steatosis to serious complications like cirrhosis. The major pathophysiological driving of NAFLD includes elevated hepatic adiposity, increased hepatic triglycerides/cholesterol, excessive hepatic inflammation, and hepatocyte ballooning injury is a common histo-pathological denominator. Although heme-oxygenase (HO) is cytoprotective, its effects on hepatocyte ballooning injury have not been reported. We investigated the effects of upregulating HO with hemin or inhibiting it with stannous-mesoporphyrin (SnMP) on hepatocyte ballooning injury, hepatic adiposity and inflammation in Zucker-diabetic-fatty rats (ZDFs), an obese type-2-diabetic model. Hemin administration to ZDFs abated hepatic/plasma triglycerides and cholesterol, and suppressed several pro-inflammatory cytokines and chemokines including, TNF-α, IL-6, IL-1β, macrophage-inflammatory-protein-1α (MIP-1α) and macrophage-chemoattractant-protein-1 (MCP-1), with corresponding reduction of the pro-inflammatory M1-phenotype marker, ED1 and hepatic macrophage infiltration. Correspondingly, hemin concomitantly potentiated the protein expression of several markers of the anti-inflammatory macrophage-M2-phenotype including ED2, IL-10 and CD-206, alongside components of the HO-system including HO-1, HO-activity and cGMP, whereas the HO-inhibitor, SnMP abolished the effects. Furthermore, hemin attenuated liver histo-pathological lesions like hepatocyte ballooning injury and fibrosis, and reduced extracellular-matrix/profibrotic proteins implicated in liver injury such as osteopontin, TGF-β1, fibronectin and collagen-IV. We conclude that hemin restore hepatic morphology by abating hepatic adiposity, suppressing macrophage infiltration, inflammation and fibrosis. The selective enhancement of anti-inflammatory macrophage-M2-phenotype with parallel reduction of pro-inflammatory macrophage-M1-phenotype and related chemokines/cytokines like TNF-α, IL-6, IL-1β, MIP-1α and MCP-1 are among the multifaceted mechanisms by which hemin restore hepatic morphology.
    PLoS ONE 01/2013; 8(11):e79270. · 3.53 Impact Factor