Evolving Strategies for Use of Phytochemicals in Prevention and Long-Term Management of Cardiovascular Diseases (CVD).

This report describes major pathomechanisms of disease in which the dysregulation of host inflammatory processes is a major factor, with cardiovascular disease (CVD) as a primary model, and reviews strategies for countermeasures based on synergistic interaction between various agents, including drugs and generally regarded as safe (GRAS) natural medical material (NMM), such as Ginkgo biloba, spice phytochemicals, and fruit seed flavonoids. The 15 well-defined CVD classes are explored with particular emphasis on the extent to which oxidative stressors and associated ischemia-reperfusion tissue injury contribute to major symptoms. The four major categories of pharmaceutical agents used for the prevention of and therapy for CVD: statins, beta blockers (ß-blockers), blood thinners (anticoagulants), and aspirin, are presented along with their adverse effects. Analyses of major cellular and molecular features of drug- and NMM-mediated cardioprotective processes are provided in the context of their development for human clinical application. Future directions of the evolving research described here will be particularly focused on the characterization and manipulation of calcium- and calcineurin-mediated cascades of signaling from cell surface receptors on cardiovascular and immune cells to the nucleus, with the emergence of both protective and pathological epigenetic features that may be modulated by synergistically-acting combinations of drugs and phytochemicals in which phytochemicals interact with cells to promote signaling that reduces the effective dosage and thus (often) toxicity of drugs.

Effects of H2S-donor ascorbic acid derivative and ischemia/reperfusion-induced injury in isolated rat hearts.

Hydrogen sulfide (H2S), a gasotransmitter, plays a crucial role in vasorelaxation, anti-inflammatory processes and mitigating myocardial ischemia/reperfusion-induced injury by regulating various signaling processes. We designed a water soluble H2S-releasing ascorbic acid derivative, BM-164, to combine the beneficial cardiovascular and anti-inflammatory effects of H2S with the excellent water solubility and antioxidant properties of ascorbic acid. DPPH antioxidant assay revealed that the antioxidant activity of BM-164 in the presence of a myocardial tissue homogenate (extract) increased continuously over the 120 min test interval due to the continuous release of H2S from BM-164. The cytotoxicity of BM-164 was tested by MTT assay on H9c2 cells, which resulted in no cytotoxic effect at concentrations of 10 to 30 µM. The possible beneficial effects of BM-164 (30 µM) was examined in isolated 'Langendorff' rat hearts. The incidence of ventricular fibrillation (VF) was significantly reduced from its control value of 79 % to 31 % in the BM-164 treated group, and the infarct size was also diminished from the control value of 28 % to 14 % in the BM-164 treated group. However, coronary flow (CF) and heart rate (HR) values in the BM-164 treated group did not show significantly different levels in comparison with the drug-free control, although a non-significant recovery in both CF and HR was observed at each time point. We attempted to reveal the mechanism of action of BM-164, focusing on the processes of autophagy and apoptosis. The expression of key autophagic and apoptotic markers in isolated rat hearts were detected by Western blot analysis. All the examined autophagy-related proteins showed increased expression levels in the BM-164 treated group in comparison to the drug-free control and/or ascorbic acid treated groups, while the changes in the expression of apoptotic markers were not obvious. In conclusion, the designed water soluble H2S releasing ascorbic acid derivative, BM-164, showed better cardiac protection against ischemia/reperfusion-induced injury compared to the untreated and ascorbic acid treated hearts, respectively.