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

Abstract

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 (β-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.

Keywords: Ginkgo biloba; cardiovascular disease; heme oxygenase; inflammation; interleukin-8; ischemia; phytochemicals; screening; sour cherry; spice.

Figure 1

High magnification micrograph of senile cardiac amyloidosis. Movat stain (black = nuclei, elastic fibres; yellow = collagen, reticular fibers; blue = ground substance, mucin; bright red = fibrin; red = muscle). Human autopsy specimen. The micrograph shows amyloid (extracellular muddy brown material—right of image), abundant lipofuscin (dark red granular material) and myocardial fibrosis (yellow—left of image). Related images Intermed. mag. (H&E). High mag. (H&E). Very high mag. (H&E). Intermed. mag. (congo red). High mag. (congo red). Very high mag. (congo red). Very high mag. (Movat’s stain). SOURCE: Wikimedia Commons, Copyright © 2011 Michael Bonert (https://en.wikipedia.org/wiki/Cardiovascular_disease#/media/File:Cardiac_amyloidosis_very_high_mag_movat.jpg (accessed on 16 May 2024)).

Figure 2

Parallel regulation of intracellular calcium-mediated hypertrophic/arrhythmogenic stimulus in cardiac myocytes and immune activation in T lymphocytes using FK506, and PAF-receptor-inhibitory ginkgolides from leaf extract (EGb761). In cardiac myocytes, the mechanical stimulation of stretch receptors and macromolecular stimulation of cell membrane-embedded Ca²⁺ channels increase cytoplasmic Ca²⁺ levels, causing calcineurin phosphatase-mediated linearization of NFAT transcription factors with resulting expression of genes contributing to hypertrophy and arrhythmogenesis [127]. An analogous process results in the activation of T lymphocytes, engendering pro-inflammatory reactions that may become pathological [128].

Figure 3

Heme oxygenase activity: reaction stoichiometry and physiological effects of product metabolites. Heme oxygenases degrade heme by cleavage of the heme ring at its alpha-methene bridge, producing carbon monoxide (CO), ferrous ion (Fe²⁺), and biliverdin, which is further reacted by biliverdin reductase to bilirubin (a major endogenous antioxidant).

Figure 4

Major pathomechanisms contributing to OA-associated articular tissue damage. Physical trauma and reactive oxygen species produced as an adaptive response by host cells increase T cell, macrophage, and synoviocyte production of pro-inflammatory cytokines, including interleukin-6 (IL-6), TNF-A, and interleukin1-beta (IL1-B). From Mahmoud FF, Al-Awadhi AM, Haines DD. Amelioration of human osteoarthritis symptoms with topical ‘biotherapeutics’: a phase I human trial. Adapted with permission from Ref. [177].