Research Interests

Cardiovascular inflammation and oxidative stress; Pro-oxidative properties and cardiovascular toxicity of anti-HIV agents (Nucleoside reverse transcriptase inhibitors & Protease Inhibitors); Endothelial modeling of drug-induced oxidative injury, apoptosis and antioxidant therapy; The role of lysosomes in iron overload and ß -drug therapy; and Magnesium, neurogenic inflammation and therapy.

Research Program

There are 3 separate research projects ongoing in our laboratory, all in the general areas of cardiovascular oxidative inflammation and therapy.
(1) Anti-HIV Nucleoside Reverse Transcriptase Inhibitor (NRTI)-Induced Cardiovascular Toxicity and the Protective Mechanisms of Magnesium (PI). This project focuses on NRTI-mediated free radical mechanisms and systemic in vivo oxidative events (e.g. neutrophil and endothelial activation, cytokines) leading to cardiovascular dysfunction (by echocardiography) and pathology by using both cultured endothelial cell and rat models. The role of iron, calcium, and the protective efficacy of Mg are investigated.
(2) Oxidative Stress and Antioxidants in Iron Overload (Co-I). This project focuses on the impact of angiotensin II receptor (AT-1 receptor) activation during iron overload using both cultured endothelial cells and small rodent models. The essential role of NADPH oxidase upregulation in conferring iron overload-mediated cardiovascular toxicity is assessed by using NADPH oxidase knockout mice. The role of the lysosome in tissue iron accumulation and the therapeutic potential of lysosomotropic ß-blockers/analogs are examined.
(3) Substance P-Mediated Cardiovascular Inflammation. (Co-I) This project investigates the central role of the neuropeptide substance P in promoting systemic inflammatory events leading to cardiac failure in Mg-deficient rats. The role of neutral endopeptidase (using NEP-/- mice) and the effect of substance P receptor blockade in influencing the pathogenesis are the main foci of this project.

Selected Publications

• Mak IT, Chmielinska JJ, Kramer JH, Weglicki WB. AZT-induced oxidative cardiovascular toxicity—attenuation by Mg-supplementation. Cardiovasc. Toxicol. In press, 2009.
• Mak IT, Kramer JH, Chmielinska JJ et al. Inhibition of neutral endopeptidase potentiates neutrophil activation during Mg-deficiency in the rat. Inflammation Res. 57: 300-305, 2008.
• Mak IT, Chmielinska JJ, Torres A, Weglicki WB. D-propranolol attenuates lysosomal iron accumulation and oxidative injury in endothelial cells. J Pharmacol Exp Ther. 317:522-508, 2006.
• Mak IT, Weglicki WB. Potent antioxidant properties of 4-OH-propranolol. J Pharmacol Exp Ther.; 308: 85-90, 2005.
• Mak IT, Goldfarb MG, Weglicki WB, Haudenschild CC. Cardiac pathologic effects of AZT in Mg-deficient mice. Cardiovasc. Toxicol 4: 169-178, 2004.
• Dickens BF, Weglicki WB, Boehme P., Mak IT. Antioxidant and lysosomotropic properties of acridine-propranolol: Protection against oxidative endothelial injury. J. Mol Cell Cardiol. 34: 129-137, 2002.