Influence of L-ascorbic acid on Chronic Hypoxia-induced alteration of Cell Signaling Pathways on Cardiovascular System in Male Wistar Rats with or without Exposure to Heavy Metal Nickel.

Abstract

Objective: To study the influence of L-ascorbic acid supplementation on the mechanisms of cardiovascular cell signaling pathways by either chronic hypoxia or heavy metal nickel exposure on the involvement of the common hypoxia signaling pathways in altered cardiovascular pathophysiology. Methods: In the present study we included forty-two adult male Albino Wistar rats (Rattus Norvegicus) and randomly allocated into seven groups and named groups as control; L ascorbic acid (50 mg / 100 gm. b.wt orally); chronic hypoxia (CH) (10% O2, 90% N2); NiSO4 (2.0 mg/100gm b.wt, i.p, every alternate day); CH + NiSO4; L-ascorbic acid + CH and L ascorbic acid + NiSO4 and respective interventions were given for 21 days. Before and after the intervention period weights of all the experimental animals were recorded and % body weight gain was calculated. Electrophysiological parameters like ECG, blood pressure (MAP) and pneumogram of animals were recorded in anaesthetized/conscious animals after the intervention period. Cardiovascular autonomic function was assessed by HRV analysis. Oxidative stress and antioxidant defence were assessed by estimating MDA, ascorbic acid, α tocopherol in the serum and MDA in heart and lung tissue homogenates by spectrophotometric methods. Oxygen sensing molecular markers like VEGF, NOS3 and NO were estimated in the serum by ELISA and immunoblotting techniques. Cardiovascular remodeling was studied by assessing cardio-somatic index, and histopathological examination of H & E stained sections of the ventricles, intramyocardial coronary artery, and elastic artery. Further, to know the vascular remodeling normalized wall index (NWI) of coronary artery was calculated. In addition to these histopathological examinations of the lung was also done. Results: Results suggest that chronic hypoxia (CH), NiSO4 and CH + NiSO4 impairs overall gravimetry of experimental animals, cardiac autonomic functions, vascular functions, induces oxidative and nitrosative stress, up regulates oxygen sensing molecular markers like VEGF and NOS3 proteins. Further, chronic hypoxia and heavy metal nickel toxicity have adverse impact on histopathology of lung, cardiac and aortic tissues. Additionally, increased NWI values support the cardiovascular remodeling. All these results indicate a possible common link between nickel toxicity and hypoxia by modulate cell signal transduction with sympathetic overactivity, oxidative stress and alteredcardiovascular pathology. Antioxidant vitamin L-ascorbic acid supplementation was able to 1) Reduce sympathetic over activity 2) reduce MAP 3) decrease oxidative stress 4) decreases nitrosative stress and 5) ameliorate cardiovascular remodeling resulting from chronic hypoxia and NiSO4 exposure. These effects of L-ascorbic acid could be attributed to its antioxidant property. Thus, the results of the present study suggest a possible use of antioxidant vitamin L-ascorbic acid supplementation as an add-on therapy against hypoxia or nickel toxicity-related pathophysiology. Conclusion: Present study shows that CH or nickel induce hypoxia cell signalling mechanisms through high production of reactive oxygen species and deprivation of antioxidant vitamins like L-ascorbic acid and alpha tocopherol, sympathetic over activity, cardiovascular, and pulmonary remodelling and hypertension. Results also indicate that heavy metal nickel induce cardiovascular pathophysiology is sensitive to oxygen hence alteration of cardiovascular anatomy and physiological function in the experimental animal by nickel or chronic hypoxia derive similar outcome. The results obtained in this study may have clinical value in humans and the effect of L-ascorbic acid on CH or nickel induced cardiovascular toxicities deserves further exploration by targeting the common transcriptional influences.