Early Perturbations in Mitochondrial Metabolism and Bioenergetics Exerted by Trypanosoma cruzi Infection in Human Cardiomyocytes

DOI: 10.1016/j.freeradbiomed.2017.10.175

162 Combination Antiretroviral Therapy (cART) Altered Redox/Nitrosative genes,

163

Enhanced Systemic Stress and Cardiac

Early Perturbations in Mitochondrial

dysfunction in HIV-1 Transgenic (HIV-Tg)

Metabolism and Bioenergetics Exerted by

Rats: Effects of Magnesium

Trypanosoma cruzi Infection in Human

Supplementation (Mg-Supp) Ivan Tong Mak1, Jay H. Kramer1, Lama Elzohary1, Joanna J Chmielinska , Chris Spurney , and William B Weglicki 1

2

George Washington University, USA

2

Children's National Medical Center, USA determined

if

clinically

Cardiomyocytes Laura María González-Ortiz1,2, Yudy Rodríguez-Avila1,3, Sandra Milena Sanabria-Barrera1,2, Ana Doris Gomez-

1

We

1

used

Granados3, María Eugenia Cárdenas Angelone4, Diego Torres-Dueñas4, Nisha J Garg5, and Marcos Lopez1,2 cART

promoted

redox/nitrosative stress and cardiac toxicity in control and

1

Fundacion Cardiovascular de Colombia, Floridablanca,

Colombia

HIV-Tg rats and the effects of Mg. Treatment with cART

2

(Truvada+atazanavir/ritonavir) up to 18 weeks, induced

Universidad del Valle, Cali, Colombia

3

significant hypomagnesemia (-25%), elevated plasma 8-

Universidad de Santander, Bucaramanga, Colombia

4

isoprostane, and RBC GSSG 2-3 folds (at 6 wks); plasma 3-

Universidad Autónoma de Bucaramanga, Colombia

5

University of Texas Medical Branch, Galveston, Texas, USA

nitrotyrosine (NT) increased 3.5-fold in the HIV-Tg rats (at 18 wks). In association, liver Nrf2 mRNA (by real time RTPCR)

was

down-regulated

75%

along

with

altered

expression of HmOX-1 and GST; however iNOS and TNFα mRNAs were increased 2- & 4-fold. Prominent ventricular NT

staining

was

observed

in

HIV-Tg+cART

rats;

echocardiography detected time-dependent moderate, but significant

decreases

in

cardiac

systolic

(Fractional

Shortening. -17%, 18 wks) and diastolic (E/A, -26%) functions.

Mg-Supp (6X normal) in diet, substantially

prevented rises in levels of 8-isoprostane, GSSG, and plasma NT. Most strikingly, Mg-Supp restored expressions of Nrf2 and HmOX-1, GST close to controls in HIV-Tg rats; both iNOS

and

TNFα

up-regulations

were

blunted.

In

association, cardiac NT staining was substantially reduced; both cardiac systolic and diastolic functional decreases were attenuated 60-70% by Mg-supp. Conclusions:

cART

treatment

synergized

with

HIV-1

expression in down-regulating Nrf2 pathway, but upregulating iNOS and TNFα expression; elevation of systemic redox/nitrosative stress contributed to cardiac dysfunction. The cardiac protective effects of Mg-Supp might be mediated by its antioxidant actions at the genomic and systemic levels through the Nrf2 pathway Supported

by

NIH

R21-HL-125038,

Genomic Supplemental Fund.

and

McCormick

Chagas’ disease is a zoonotic disease caused by Trypanosoma cruzi infection that is endemic in Mexico, Central and South America. Usually, the disease is transmitted by a triatomine vector and domestic and wild mammals that serve as reservoirs for this parasitic protozoan. However, due to increased immigration, individuals with the disease have been identified in developed countries like the USA, Canada and

Europe,

increasing

the

possibility

of

secondary

transmission routes of T. cruzi via organ transplantation, blood transfusions and maternal-fetal transmission. The clinical course of the disease is divided into the acute and chronic phases. While the acute infection is mildly asymptomatic and often misdiagnosed, the chronic phase usually manifests as cardiomyopathy with a wide spectrum of

manifestations,

ranging

from

minor

myocardium

involvement to left ventricular (LV) systolic dysfunction, dilated

cardiomyopathy,

arrhythmias,

thromboembolic

events, and terminal cardiac failure. Interestingly, because chagasic hearts are virtually free of parasites, and the etiology of chronic Chagas disease remains under heavy discussion. The B and T cell immunity in combination with mitochondrial

dysfunction,

inflammatory

cytokines/chemokines, and oxidative stress are the hallmark of the disease. In this work, we aimed to elucidate the early metabolic perturbations exerted by T. cruzi (Sylvio X10) infection in AC16 human cardiomyocytes. In addition, we

SfRBM 2017

117

also examined the role of innate immunity by co-treating

reductase activity were analyzed in blood samples. In black

cells with pro-inflammatory proteins and cytokines known

men, ambulatory pulse pressure was negatively associated

to have a role in the infection process like IFN-γ, TNF-α and

with glutathione peroxidase activity (R2 = 0.19; β = -0.25;

IL-6. Early changes in metabolism and mitochondrial

p = 0.026). Black and white women displayed positive

bioenergetics were assessed in real time with a Seahorse

associations of ambulatory systolic blood pressure and

XFe24 Extracellular Flux Analyzer. We found that T. cruzi

ambulatory

infection alone, was not enough to induce significant

reductase activity while white men displayed a positive

mean

arterial

pressure

with

glutathione

changes in mitochondrial metabolism and bioenergetics and

association of ambulatory pulse pressure with glutathione

to increase ROS generation in human cardiomyocytes.

reductase activity. The lower glutathione peroxidase activity

However, T. cruzi infection in combination with IFN-γ, TNF-

and total antioxidant status, the higher reactive oxygen

α and IL-6 exerted a drastic effect in cardiomyocyte

species as well as the negative association between

mitochondrial bioenergetics and ROS production, suggesting

ambulatory pulse pressure and glutathione peroxidase

that innate immunity plays a key role in Chagas-induced

activity in the black men suggest that oxidative stress is

cardiomyopathy.

associated with early vascular changes in this group. In the other three groups, the positive associations of blood pressure with glutathione reductase activity suggest a

DOI: 10.1016/j.freeradbiomed.2017.10.176

possible role for adequate glutathione reductase activity in preventing or delaying the development of hypertension. DOI: 10.1016/j.freeradbiomed.2017.10.177

164 The Relation of blood pressure and carotid intima-media

thickness

with

the

glutathione cycle in a young bi-ethnic population: The African-PREDICT study

Effect of Nitrite and N-acetylcysteine

Caitlynd Myburgh1,2, Catharina MC Mels1,3, and Hugo W Huisman1,3 1

Hypertension in Africa Research Team (HART), South

Africa

Treatment on Blood Pressure, Arterial Stiffness and Vascular Function in Spontaneously Hypertensive Rats Enika Nagababu1, Jochen Steppan1, Lakshmi Santhanam1,

2

University of South Africa (UNISA), South Africa

3

MRC Research Unit for Hypertension and Cardiovascular

Disease, North-West University, South Africa Oxidative stress has been implicated in the development of hypertension, arterial stiffness and atherosclerosis. Optimal functioning of the enzymatic antioxidant system is central to prevent increased oxidative stress and its consequences. We aimed to investigate the relationships of ambulatory blood pressure and carotid intima-media thickness with enzyme activities of the glutathione cycle in young, healthy black and white South Africans. This study included 396 participants (black men (N = 89), white men (N = 78), black women (N = 105) and white women (N = 124)) of the African-PREDICT study aged 20-30 years. Ambulatory blood pressure and carotid intima-media thickness were measured, while glutathione peroxidase and glutathione

118

165

Steven M Frank1, and Dan E Berkowitz1 1

Johns Hopkins Medical Institutions, USA

Introduction: Reduced nitric oxide (NO) bioavailability and increased generation of reactive oxygen species and inflammation with advancing age play a major role in the development of cardiovascular disease (CVD) risk factors of hypertension, endothelial dysfunction and arterial stiffness. Therefore, increase in NO bioavailability by supplementing inorganic nitrite and improve in antioxidant defense system by supplementing N-acetylcysteine (NAC) could protect against the CVD. Hypertension is highly prevalent in a population and cause endothelial dysfunction and arterial stiffness. Hence spontaneously hypertensive rats (SHR) were used in this study as a model for hypertension-mediated endothelial dysfunction and arterial stiffness.

SfRBM 2017