Kinobe, Robert T., Phie, James, Haleagrahara, Nagaraja, and Chilton, Lisa (2016) Carbon monoxide releasing molecule-3 alleviates angiotensin II-induced hypertrophy and apoptosis by inhibiting oxidative and endoplasmic reticulum stress in H9c2 cardiomyocytes. FASEB Journal, 30 (1).

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Abstract

Heme oxygenase-1 (HO-1) is an inducible, ubiquitously expressed enzyme catalyzing the catabolism of heme to generate bilirubin and biliverdin (potent antioxidants), carbon monoxide (a gaseous signalling anti-inflammatory molecule) and iron. However, the putative protective role of HO-1 in cardiovascular disease seems to be context dependent and paradoxical in nature. In previous studies we showed that the alpha-myosin heavy chain restricted cardiac overexpression of HO-1 exacerbated hypertension-induced heart failure with aging but was protective in acute, isoproterenol-induced cardiomyopathy in mice. In the present study we investigated the specific role and effects of a carbon monoxide releasing molecule-3 (CORM-3) on angiotensin (Ang) II-induced hypertrophy and apoptosis in H9c2 cardiomyocytes. Cell hypertrophy, viability and apoptosis were quantified by measuring cell surface area, mitochondrial reduction of diphenyltetrazolium and caspase-3 activity respectively. Oxidative stress was detected by intracellular dichlorofluorescein fluorescence and superoxide-mediated reduction of ferricytochrome c at 550 nm. Application of CORM-3 significantly inhibited Ang II-induced production of reactive oxygen intermediates, cell hypertrophy and apoptosis (P < 0.05). The cytoprotective effects of CORM-3 were associated with a significant (P < 0.001), dose-dependent reduction in Ang II-induced endoplasmic reticulum (ER) stress as quantified by the expression of calreticulin in ELISA assays (Supplemental Figure 1). Mean calreticulin expression values (ng/mg) were Control: 11 ± 5; Ang II: 179 ± 43; Ang II and 10 μM CORM-3: 77 ± 18; Ang II and 50 μM CORM-3: 41 ± 11; CORM-3 only: 16 ± 7. The protective effects of CORM-3 were abrogated by pre-releasing the carbon monoxide in solution. These data demonstrate that application of physiological concentrations of carbon monoxide may be a useful therapeutic strategy against cardiovascular disease and heart failure as Ang II-induced oxidative and ER stress are important hallmarks of these conditions.

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