Oxygen cycling in conjunction with stem cell transplantation induces NOS3 expression leading to attenuation of fibrosis and improved cardiac function

Khan, Mahmood; Meduru, Sarath; Gogna, Rajan; Madan, Esha; Citro, Lucas; Kuppusamy, M. Lakshmi; Sayyid, Muzzammil; Mostafa, Mahmoud; Hamlin, Robert L.; Kuppusamy, Periannan

doi:10.1093/cvr/cvr277

Cited by 34 publications

(45 citation statements)

References 45 publications

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“…Assessment of cardiac function was performed at the baseline and at 4 weeks after MI or stem cell transplantation. Rats were anesthetized using 1.5-2% isoflurane, and M-mode ultrasound images were acquired using a Vevo 2100 (VisualSonics, Toronto, ON, Canada) ultrasonic rodent imaging system as described previously (Khan et al, 2012).…”

Section: Methodsmentioning

confidence: 99%

“…Immunostaining was performed in formalin-fixed paraffin-embedded heart sections (5-m). The fixed tissue sections were serially rehydrated as described previously (Khan et al, 2012). The tissue sections were then incubated with 2% goat serum and 5% bovine serum albumin in PBS to reduce nonspecific binding.…”

Section: Methodsmentioning

confidence: 99%

“…Western blots for phosphorylated Akt, phosphorylated extracellular signalregulated kinase (ERK)1/2, Bcl-2, and caspase-3 signaling were performed with the tissue homogenates as described previously (Khan et al, 2012). The anterior walls of the left ventricles were collected from sham, MI, Carv, MSC, and MSCϩCarv groups.…”

Section: Methodsmentioning

confidence: 99%

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Carvedilol Enhances Mesenchymal Stem Cell Therapy for Myocardial Infarction via Inhibition of Caspase-3 Expression

Hassan

Meduru

Taguchi

et al. 2012

J Pharmacol Exp Ther

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Adult stem cells have shown great promise toward repairing infarcted heart and restoring cardiac function. Mesenchymal stem cells (MSCs), because of their inherent multipotent nature and their ability to secrete a multitude of growth factors and cytokines, have been used for cardiac repair with encouraging results. Preclinical studies showed that MSCs injected into infarcted hearts improve cardiac function and attenuate fibrosis. Although stem cell transplantation is a promising therapeutic option to repair the infarcted heart, it is faced with a number of challenges, including the survival of the transplanted cells in the ischemic region, due to excessive oxidative stress present in the ischemic region. The objective of this study was to determine the effect of Carvedilol (Carv), a nonselective ␤-blocker with antioxidant properties, on the survival and engraftment of MSCs in the infarcted heart. MSCs were subjected to a simulated host-tissue environment, similar to the one present in the infarcted myocardium, by culturing them in the presence of hydrogen peroxide (H 2 O 2 ) to induce oxidative stress. MSCs were treated with 2.5 M Carv for 1 h in serum-free medium, followed by treatment with H 2 O 2 for 2 h. The treated cells exhibited significant protection against H 2 O 2 -induced cell death versus untreated controls as determined by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays. Likewise, transplantation of MSCs after permanent left coronary artery ligation and treatment of animals after myocardial infarction (MI) with Carv (5 mg/kg b.wt.) led to significant improvement in cardiac function, decreased fibrosis, and caspase-3 expression compared with the MI or MSC-alone groups.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Carvedilol Enhances Mesenchymal Stem Cell Therapy for Myocardial Infarction via Inhibition of Caspase-3 Expression

Hassan

Meduru

Taguchi

et al. 2012

J Pharmacol Exp Ther

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“…We have recently demonstrated that pharmacological treatment of MSCs with either trimetazidine (Vastrel  ) [59] or hyperbaric oxygen [60,61] results in significantly higher efficiencies in attenuating cardiac fibrosis and improving cardiac function than the untreated cells. These improvements in the infarcted hearts were linked to up-regulation of survival signaling such as pAkt and Bcl-2 [59], increased graft survival, VEGF, NOS3 activation, and angiogenesis [60,61], which may contribute to the enhanced anti-fibrotic effects of the modified cells. Moreover, preconditioning of adipose-derived stem cells with a phosphodiesterase inhibitor, sildenafil (Viagra  ), increased their viability and enhanced the release of pro-angiogenic/pro-survival growth factors such as VEGF, FGF, IGF and angiopoietin-1 both in vitro and in vivo [62].…”

Section: Stem Cell Modifications and Cardiac Fibrosismentioning

confidence: 99%

Stem cell transplantation as a therapy for cardiac fibrosis

Elnakish

Kuppusamy

Khan

2012

The Journal of Pathology

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Cardiac fibrosis is a fundamental constituent of most cardiac pathologies and represents the upshot of nearly all types of cardiac injury. Generally, fibrosis is a scarring process, characterized by accumulation of fibroblasts and deposition of increasing amounts of extracellular matrix (ECM) proteins in the myocardium. Therapeutic approaches that control fibroblast activity and evade maladaptive processes could represent a potential strategy to attenuate progression towards heart failure. Currently, cell therapy is actively perceived as an alternative to traditional pharmacological management of myocardial infarction (MI). The majority of the studies applying stem cell therapy following MI have demonstrated a decline in fibrosis. However, it was not clearly recognized whether the decline in cardiac fibrosis was due to replacement of dead cardiomyocytes or because of the direct effects of paracrine factors released from the transplanted stem cells on the ECM. Therefore, the main focus of this review is to discuss the impact of different types of stem cells on cardiac fibrosis and associated cardiac remodelling in a variety of experimental models of heart failure, particularly MI.

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“…In vitro, TGFβ expression and secretion by fibroblasts has been shown to be decreased in response to HBOT (12,58). A reduction of fibrosis by HBOT has been demonstrated in animal models of laminectomy, tracheal anastomosis and myocardial infarction (59)(60)(61), although in a tendon healing model, HBOT seemed to enhance fibrosis (62).…”

Section: Continued On Next Pagementioning

confidence: 99%

Gene Expression Analysis Reveals Inhibition of Radiation-Induced TGFβ-Signaling by Hyperbaric Oxygen Therapy in Mouse Salivary Glands

Spiegelberg

Swagemakers

IJcken

et al. 2014

Mol Med

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A side effect of radiation therapy in the head and neck region is injury to surrounding healthy tissues such as irreversible impaired function of the salivary glands. Hyperbaric oxygen therapy (HBOT) is clinically used to treat radiation-induced damage but its mechanism of action is largely unknown. In this study, we investigated the molecular pathways that are affected by HBOT in mouse salivary glands two weeks after radiation therapy by microarray analysis. Interestingly, HBOT led to significant attenuation of the radiation-induced expression of a set of genes and upstream regulators that are involved in processes such as fibrosis and tissue regeneration. Our data suggest that the TGFβ-pathway, which is involved in radiation-induced fibrosis and chronic loss of function after radiation therapy, is affected by HBOT. On the longer term, HBOT reduced the expression of the fibrosis-associated factor α-smooth muscle actin in irradiated salivary glands. This study highlights the potential of HBOT to inhibit the TGFβ-pathway in irradiated salivary glands and to restrain consequential radiation induced tissue injury.

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Oxygen cycling in conjunction with stem cell transplantation induces NOS3 expression leading to attenuation of fibrosis and improved cardiac function

Abstract: The results showed that post-MI exposure of rats to daily cycles of hyperoxygenation (oxygen cycling) improved stem cell engraftment, cardiac function, and increased NOS3 expression.

Cited by 34 publications

References 45 publications

Carvedilol Enhances Mesenchymal Stem Cell Therapy for Myocardial Infarction via Inhibition of Caspase-3 Expression

Carvedilol Enhances Mesenchymal Stem Cell Therapy for Myocardial Infarction via Inhibition of Caspase-3 Expression

Stem cell transplantation as a therapy for cardiac fibrosis

Gene Expression Analysis Reveals Inhibition of Radiation-Induced TGFβ-Signaling by Hyperbaric Oxygen Therapy in Mouse Salivary Glands

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