Cardiovascular Journal of Africa: Vol 25 No 5 (September/October 2014)

CARDIOVASCULAR JOURNAL OF AFRICA • Volume 25, No 5, September/October 2014

212

AFRICA

Effects of rosuvastatin on ADMA, rhokinase, NADPH

oxidase, caveolin-1, hsp 90 and NFkB levels in a rat

model of myocardial ischaemia–reperfusion

Oktay Burma, Elif Onat, Ayhan Uysal, Necip Ilhan, Deniz Erol, Mete Ozcan, Engin Sahna

Abstract

Aim:

Endothelial dysfunction, oxidative stress and inflam-

mation are among the most important mechanisms of

ischaemia–reperfusion (I/R) injury. Besides their cholesterol-

lowering effects, statins are known to provide protection

against myocardial dysfunction and vascular endothelial

injury via nitric oxide-dependent mechanisms. The aim of this

study was to investigate the effects of rosuvastatin on certain

intermediates involved in the generation of nitric oxide

(asymmetrical dimethyl arginin, ADMA, caveolin-1 and

hsp 90), oxidative stress (rhokinase, NADPH oxidase) and

inflammation (NFkB), using an

in vivo

model of myocardial

infarction in the rat.

Methods:

Adult male Sprague Dawley rats were divided into

three groups (control, I/R and I/R after 15 days of rosuvas-

tatin administration). Reperfusion was applied for 120 min

following left anterior descending coronary artery ischaemia

for 30 min. Caveolin-1, hsp 90 and NFkB levels were evalu-

ated with the quantitative reverse transcriptase polymerase

chain reaction (qRT-PCR) and ADMA, rhokinase and

NADPH oxidase levels were evaluated with ELISA.

Results:

While NFkB and hsp 90 levels were higher in the I/R

group, their levels were significantly lower in the rosuvastatin

group. While ADMA and NADPH oxidase levels significantly

increased with I/R, they were lower in the rosuvastatin-treated

group, but not statistically significant. Rhokinase levels were

significantly lower in the rosuvastatin group. Caveolin-1 levels

were not different between the groups.

Conclusion:

Our results suggest that ADMA, rhokinase,

NADPH oxidase, hsp 90 and NFkB could facilitate I/R

injury, and rosuvastatin significantly reduced levels of these

parameters. These results indicate that rosuvastatin may

have a protective role in I/R injury via mechanisms targeting

inflammation, endothelial dysfunction and oxidative stress.

Keywords:

ischaemia–reperfusion, rosuvastatin, oxidative stress,

ADMA, hsp 90, caveolin-1, NFkB, rhokinase, NADPH oxidase

Submitted 5/2/14, accepted 25/6/14

Cardiovasc J Afr

2014;

: 212–216

www.cvja.co.za

DOI: 10.5830/CVJA-2014-038

Ischaemic heart disease remains among the major causes of

morbidity and mortality worldwide. The most common form is

reduction in blood flow in the coronary arteries supplying blood

to the myocardium due to atherosclerotic plaques or vasospasm.

After ischaemia, reperfusion of the tissue is of great importance

for maintenance of the viability of the ischaemic tissue. However

reperfusion may paradoxically lead to some morphological

changes, enzyme destruction and even death of the still-viable

tissue that may be rescued.

Ischaemia–reperfusion (I/R) injury is the mainstay of

myocardial infarction, cerebral ischaemia, stroke, haemorrhagic

shock and surgical interventions such as organ transplantation,

cardiac surgery, coronary angioplasty and thrombolytic

treatment-related pathophysiology.

Endothelial dysfunction,

oxidative stress and inflammation are among the most common

mechanisms of I/R injury.

4,5

Asymmetrical dimethyl arginine (ADMA) is an endogenous

nitric oxide synthase (eNOS) inhibitor. Its importance is

becoming more recognised and further studies are required

to determine its use in clinical diagnosis. Available evidence

indicates that oxidative stress leads to changes in the activity

of enzymes involved in the production and degradation of

ADMA.

4,5

High levels of ADMA and low levels of nitric oxide

(NO) in the coronary arteries of patients with vasospastic angina

have been reported.

In the cardiovascular system, NADPH oxidase accounts

for the production of reactive oxygen species (ROS), which is

produced not only during I/R injury but also under physiological

conditions.

The pro-oxidative NADPH oxidase is present in

the plasma membranes of neutrophils, which are an important

source of free radical formation and I/R injury.

Additionally, the

rhokinase pathway, which has an important role in regulation

of vascular smooth muscle tone, has been shown to be involved

in I/R injury, thus making its inhibition a potential target for

limiting I/R injury.

Department of Cardiovascular Surgery, Faculty of

Medicine, University of Firat, Elazig, Turkey

Oktay Burma, MD,

oburma@hotmail.com

Ayhan Uysal, MD

Department of Pharmacology, Faculty of Medicine,

University of Firat, Elazig, Turkey

Elif Onat, MD

Engin Sahna, MD

Department of Biochemistry, Faculty of Medicine,

University of Firat, Elazig, Turkey

Necip Ilhan, MD

Department of Medical Genetics, Faculty of Medicine,

University of Firat, Elazig, Turkey

Deniz Erol, MD

Department of Biophysics, Faculty of Medicine, University

of Firat, Elazig, Turkey

Mete Ozcan, MD