Changes in neurofilament 200 and tyrosine hydroxylase expression in the cardiac innervation of diabetic rats during aging

Bakovic, Marija; Filipović, Natalija; Hamzić, Lejla Ferhatović; Kunac, Nenad; Zdrilic, Elena; Uljević, Marija Vitlov; Kostić, Sandra; Puljak, Livia; Vukojević, Katarina

doi:10.1016/j.carpath.2017.11.003

Cited by 11 publications

(15 citation statements)

References 18 publications

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“…Our previous results have shown an initial increase of the NF200 fiber density 2 weeks after induction of diabetes mellitus by streptozocin injection in Sprague-Dawley rats, which was followed by a decrease 12 months after induction [31]. This is also consistent with our results considering that we found a significant increase in NF200-immunoreactive fibers in the STZ induced diabetic group compared to the control group in the subendocardial tissue of the septum facing right ventricle.…”

Section: Discussionsupporting

confidence: 93%

“…It was found that sympathetic nerve remodeling predominates during 10-weeks of STZ-induced diabetes [45]. In our previous study, we found the largest increase of TH fiber density in the rat heart 2 months after induction of the DM1 model, with the beginning of the proliferation of sympathetic nerve terminals already 2 weeks after induction of DM and there was no change detected in the later stages of DM (6 and 12 months) [31]. This is consistent with our finding of a significant increase of TH fibers density in the subendocardial area one month after DM1 induction.…”

Section: Discussionmentioning

confidence: 71%

“…As previously proven, changes in sensory and sympathetic innervation density in rat hearts with different stages of experimental DM occur [31,32]. The effects of PUFAs on cardiovascular and nervous systems have been intensively explored, but many inconsistencies about the effects of n3 and/or n6 PUFAs on the cardiovascular system, noted through clinical and experimental studies, require further investigation of the mechanisms of their effects and possible side-effects [13][14][15].…”

Section: Discussionmentioning

confidence: 90%

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Effects of Different n6/n3 PUFAs Dietary Ratio on Cardiac Diabetic Neuropathy

Urlić

Urlic

et al. 2020

Nutrients

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We studied the influence of experimentally induced DM1, in combination with different dietary n6:n3 polyunsaturated fatty acid (PUFA) ratios on different types of nerve fibers in rat myocardium, in order to reveal whether protective/unfavorable effects of different PUFAs on myocardial function in diabetic patients could be a (partial) repercussion of their effect on the changes in cardiac innervation. The control group (c) and diabetic group (stz) were fed with an n6/n3 ratio of ≈7; the diet of the stz+n6 group had an n6/n3 ratio ≈60, while the diet for the stz+DHA group contained 2.5% of fish oil (containing 16% eicosapentaenoic acid—EPA and 19% docosahexaenoic acid—DHA), n6/n3 ratio of ≈1. DM1 was induced by i.p. injection of streptozotocin (55 mg/kg) and rats were euthanized 30 days after induction. Immunohistochemistry was used for the detection and quantification of different types of neuronal fibers in the cardiac septum. We found changes in cardiac innervations characteristics for the initial phase of experimental DM1, which manifested as an increase in total number and area density of all neuronal fibers, measured by Pgp9.5 immunoreactivity. By detailed analysis, we found that this increase consisted mostly of heavy myelinated NF200 immunoreactive fibers and TH immunoreactive sympathetic fibers, while the density of ChAT immunoreactive parasympathetic fibers decreased. In the deep (middle) part of the myocardium, where rare fibers (of all studied types) were found, significant differences were not found. Surprisingly, we found a more consistent protective effect of n6 PUFAs, in comparison to n3 PUFAs supplementation. These results may provide a better understanding of the potential impacts of different PUFA ratios in the diet of diabetic patients on cardiac innervation and genesis and outcome of diabetic autonomic cardiomyopathy.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 90%

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Effects of Different n6/n3 PUFAs Dietary Ratio on Cardiac Diabetic Neuropathy

Urlić

Urlic

et al. 2020

Nutrients

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“…In line with these findings, Otake et al [45] demonstrated a higher density of sympathetic nerves in diabetic rats. Also, Bakovic et al [46] demonstrated that the increased sympathetic nerve fiber density in diabetic hearts started 2 weeks after induction of DM and reaching its peak after 2 months, then declined 6 to 12 months after DM induction. Also, a recent study by Hussein and colleagues demonstrated similar findings [9].…”

Section: Discussionmentioning

confidence: 99%

Comparative Study of the Effects of GLP1 Analog and SGLT2 Inhibitor against Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms

et al. 2020

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The present study investigated the possible cardioprotective effects of GLP1 and SGLT2i against diabetic cardiomyopathy (DCM) in type 2 diabetic rats and the possible underlying mechanisms. Methods: Thirty-two male Sprague Dawley rats were randomly subdivided into 4 equal groups: (a) control group, (b) DM group, type 2 diabetic rats with saline daily for 4 weeks, (c) DM + GLP1, as DM group with GLP1 analogue (liraglutide) at a dose of 75 µg/kg for 4 weeks, and (d) DM + SGLT2i as DM group with SGLT2 inhibitor (dapagliflozin) at a dose of 1 mg/kg for 4 weeks. By the end of treatment (4 weeks), serum blood glucose, homeostasis model assessment insulin resistance (HOMA-IR), insulin, and cardiac enzymes (LDH, CK-MB) were measured. Also, the cardiac histopathology, myocardial oxidative stress markers (malondialdehyde (MDA), glutathione (GSH) and CAT) and norepinephrine (NE), myocardial fibrosis, the expression of caspase-3, TGF-β, TNF-α, and tyrosine hydroxylase (TH) in myocardial tissues were measured. Results: T2DM caused significant increase in serum glucose, HOMA-IR, serum CK-MB, and LDH (p < 0.05). Also, DM caused significant myocardial damage and fibrosis; elevation of myocardial MDA; NE with upregulation of myocardial caspase-3, TNF-α, TGF-β, and TH; and significant decrease in serum insulin and myocardial GSH and CAT (p < 0.05). Administration of either GLP1 analog or SGLT2i caused a significant improvement in all studied parameters (p < 0.05). Conclusion: We concluded that both GLP1 and SGLT2i exhibited cardioprotective effects against DCM in T2DM, with the upper hand for SGLT2i. This might be due to attenuation of fibrosis, oxidative stress, apoptosis (caspase-3), sympathetic nerve activity, and inflammatory cytokines (TNF-α and TGF-β).

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“…Peripheral nerve degeneration in diabetic neuropathy, a major complication of diabetes with a frequency of 25-60%, has been attributed to multifactorial mechanisms, such as metabolic dysregulation of sorbitol, oxidative stress and neurotrophic deficiency, according to studies on experimental diabetes in rodents and human nerve pathology ( Zochodne, 1999 ; Brownlee, 2001 ; Kennedy and Zochodne, 2005 ; Edwards et al, 2008 ; Bakovic et al, 2018 ). Although microangiopathy is listed as one of the major microvascular complications of diabetes, including reduced endoneurial capillary density and endothelial dysfunction, the cascades leading to this cellular pathology and its molecular consequences in diabetic nerves have not yet been systemically investigated.…”

Section: Introductionmentioning

confidence: 99%

CD40-mediated HIF-1α expression underlying microangiopathy in diabetic nerve pathology

Kan

Hsieh

Chien

et al. 2018

Disease Models &Amp; Mechanisms

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To understand the pathology and molecular signatures of microangiopathy in diabetic neuropathy, we systemically and quantitatively examined the morphometry of microvascular and nerve pathologies of sural nerves. In the endoneurium of diabetic nerves, prominent microangiopathy was observed, as evidenced by reduced capillary luminal area, increased capillary basement membrane thickness and increased proportion of fibrin(+) blood vessels. Furthermore, capillary basement membrane thickness and the proportion of fibrin(+) blood vessels were correlated with small myelinated fiber density in diabetic nerves. In diabetic nerves, there was also significant macrophage and T cell infiltration, and cluster of differentiation 40 (CD40) expression was increased. The molecular alterations observed were upregulation of hypoxia-inducible factor-1α (HIF-1α), mitogen-activated protein kinase-activated protein kinase 2 (MK2; MAPKAPK2) and phosphatase and tensin homolog (PTEN). In addition, HIF-1α was correlated with small myelinated fiber density and capillary luminal area, while both MK2 and PTEN were correlated with capillary basement membrane thickness. The molecular cascades were further demonstrated and replicated in a cell model of microangiopathy on human umbilical vein endothelial cells (HUVECs) exposed to high-glucose medium by silencing of CD40, PTEN and HIF-1α in HUVECs using shRNA. These data clarified the hierarchy of the molecular cascades, i.e. upregulation of CD40 leading to HIF-1α expression in endothelium and nerve fibers. In conclusion, this study revealed the association of microangiopathy, thrombosis and inflammatory infiltrates with nerve degeneration in diabetic nerves, demonstrating that CD40 is a key molecule for the upregulation of HIF-1α and PTEN underlying the severity of microangiopathy.

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Changes in neurofilament 200 and tyrosine hydroxylase expression in the cardiac innervation of diabetic rats during aging

Cited by 11 publications

References 18 publications

Effects of Different n6/n3 PUFAs Dietary Ratio on Cardiac Diabetic Neuropathy

Effects of Different n6/n3 PUFAs Dietary Ratio on Cardiac Diabetic Neuropathy

Comparative Study of the Effects of GLP1 Analog and SGLT2 Inhibitor against Diabetic Cardiomyopathy in Type 2 Diabetic Rats: Possible Underlying Mechanisms

CD40-mediated HIF-1α expression underlying microangiopathy in diabetic nerve pathology

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