Concise Review: Challenges in Regenerating the Diabetic Heart: A Comprehensive Review

Satthenapalli, Venkata R.; Lamberts, Regis R.; Katare, Rajesh

doi:10.1002/stem.2661

Cited by 11 publications

(12 citation statements)

References 196 publications

(241 reference statements)

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“…The association hyperglycemia/ROS/cellular senescence represents a major cause of inefficiency of regenerative medicine [9, 10, 56, 57]. Further, clinical trials established that an altered glycemic control is equal to therapeutic failure [13, 14].…”

Section: Discussionmentioning

confidence: 99%

L-Carnitine: An Antioxidant Remedy for the Survival of Cardiomyocytes under Hyperglycemic Condition

Vacante

Senesi

Montesano

et al. 2018

Journal of Diabetes Research

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Background Metabolic alterations as hyperglycemia and inflammation induce myocardial molecular events enhancing oxidative stress and mitochondrial dysfunction. Those alterations are responsible for a progressive loss of cardiomyocytes, cardiac stem cells, and consequent cardiovascular complications. Currently, there are no effective pharmacological measures to protect the heart from these metabolic modifications, and the development of new therapeutic approaches, focused on improvement of the oxidative stress condition, is pivotal. The protective effects of levocarnitine (LC) in patients with ischemic heart disease are related to the attenuation of oxidative stress, but LC mechanisms have yet to be fully understood. Objective The aim of this work was to investigate LC's role in oxidative stress condition, on ROS production and mitochondrial detoxifying function in H9c2 rat cardiomyocytes during hyperglycemia. Methods H9c2 cells in the hyperglycemic state (25 mmol/L glucose) were exposed to 0.5 or 5 mM LC for 48 and 72 h: LC effects on signaling pathways involved in oxidative stress condition were studied by Western blot and immunofluorescence analysis. To evaluate ROS production, H9c2 cells were exposed to H2O2 after LC pretreatment. Results Our in vitro study indicates how LC supplementation might protect cardiomyocytes from oxidative stress-related damage, preventing ROS formation and activating antioxidant signaling pathways in hyperglycemic conditions. In particular, LC promotes STAT3 activation and significantly increases the expression of antioxidant protein SOD2. Hyperglycemic cardiac cells are characterized by impairment in mitochondrial dysfunction and the CaMKII signal: LC promotes CaMKII expression and activation and enhancement of AMPK protein synthesis. Our results suggest that LC might ameliorate metabolic aspects of hyperglycemic cardiac cells. Finally, LC doses herein used did not modify H9c2 growth rate and viability. Conclusions Our novel study demonstrates that LC improves the microenvironment damaged by oxidative stress (induced by hyperglycemia), thus proposing this nutraceutical compound as an adjuvant in diabetic cardiac regenerative medicine.

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Section: Discussionmentioning

confidence: 99%

L-Carnitine: An Antioxidant Remedy for the Survival of Cardiomyocytes under Hyperglycemic Condition

Vacante

Senesi

Montesano

et al. 2018

Journal of Diabetes Research

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“…Cardiovascular disease (CVD) is the main cause of morbidity and mortality in diabetic patients, accounting for about 80% of all diabetic deaths in North America [ 214 , 215 ]. DM has a dramatic impact on the aging and senescence of different types of adult stem cells [ 216 ]. In particular, DM impairs the in vitro proliferative and differentiation potential of adult CSCs, further worsening their senescence phenotype even when compared with CSCs from non-diabetic ischemic patients [ 217 ].…”

Section: Csc Senescence and Diabetic Cardiomyopathymentioning

confidence: 99%

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

Cianflone

Torella

Biamonte

et al. 2020

Cells

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Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.

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“…A pioneer work done by Salabei and co‐workers showed that HGC had prominent effect on CPCs glucose metabolism and glycolysis by modulating the activity of enzyme PFKFB3, contributed to a reduced mitochondrial activity . Uncontrolled glycolysis activation in CPCs elevates the generation of reactive oxygen species and accumulation of methylglyoxal, advanced glycation end product, inside CPCs . The occurrence of diabetic condition predisposes CPCs entering aging via the modulation of telomeric shortening and the activation of P53 and p16 INK4a .…”

Section: Discussionmentioning

confidence: 99%

“…29 Uncontrolled glycolysis activation in CPCs elevates the generation of reactive oxygen species and accumulation of methylglyoxal, advanced glycation end product, inside CPCs. [29][30][31] The occurrence of diabetic condition predisposes CPCs entering aging via the modulation of telomeric shortening and the activation of P53 and p16 INK4a . [32][33][34][35][36] In our previous work, a decrease in the total level of Akt factor was evident in EPCs after 7-day treatment with serum from diabetic subjects.…”

Section: Discussionmentioning

confidence: 99%

High glucose condition limited the angiogenic/cardiogenic capacity of murine cardiac progenitor cells in in vitro and in vivo milieu

Khaksar

Sayyari

Rezaie

et al. 2018

Cell Biochemistry & Function

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Murine c-kit cardiac cells were isolated and enriched by magnetic activated cell sorting technique. c-kit cells viability and colony-forming activity were evaluated by MTT and clonogenic assay. c-kit cells were exposed to endothelial, pericyte, and cardiomyocyte induction media containing 30mM glucose for 7 days. We monitored the level of endothelial (VE-cadherin, CD31, and vWF), pericyte (NG , α-SMA, and PDGFR-β), and cardiomyocyte markers (cTnT) using flow cytometry, real-time Polymerase Chain Reaction (PCR), and Enzyme-Linked Immunosorbent Assay (ELISA) analyses. Ultrastructural changes were studied by transmission electron microscopy (TEM) in cells treated with 5-Azacytidine and 30mM glucose. Matrigel plug assay was performed to determine the angio/cardiogenic property of c-kit cells in a diabetic mouse model. Glucose of 30mM decreased c-kit cells viability and clonogenicity (P < 0.05). The transdifferentiation capacity of c-kit cells into the endothelial lineage, pericytes, and cardiomyocytes were reduced through the inhibition of related genes (P < 0.05). TEM analysis revealed cardiomyocyte differentiation rate in c-kit cells coincided with an increased intracellular lipid accumulation and reduced number of mitochondria. Similar to in vitro condition, the angiogenic capacity of c-kit cells was aborted in vivo indicated by reduced NG , α-SMA, CD31, and vWF levels. High glucose condition reduces the angio/cardiogenic capacity of cardiac c-kit cells in vitro and in vivo. SIGNIFICANCE OF THE STUDY: High glucose condition seen in diabetes mellitus could affect the regenerative potential of cardiac tissue. The current experiment showed that the exposure of murine cardiac progenitor cells (CD117 cells) to condition containing 30mM glucose could decrease the differentiation properties into endothelial cells, pericytes, and mature cardiomyocytes in vitro and in vivo. Our finding confirmed that the angiogenic/cardiogenic potential cardiac progenitor cells decrease under treatment with high glucose content as seen in the diabetic condition.

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Concise Review: Challenges in Regenerating the Diabetic Heart: A Comprehensive Review

Cited by 11 publications

References 196 publications

L-Carnitine: An Antioxidant Remedy for the Survival of Cardiomyocytes under Hyperglycemic Condition

L-Carnitine: An Antioxidant Remedy for the Survival of Cardiomyocytes under Hyperglycemic Condition

Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease

High glucose condition limited the angiogenic/cardiogenic capacity of murine cardiac progenitor cells in in vitro and in vivo milieu

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