Hydroxysafflor yellow a and the cardiac permeability transition pore

Abstract

Coronary heart disease is a leading cause of death worldwide, causing a reduction in blood flow that leads to damage of heart tissue. Much of this damage occurs via opening of the mitochondrial permeability transition pore (MPTP). Preventing this pore's opening is therefore a useful therapeutic goal in treating cardiovascular disease. Hydroxysafflor yellow A (HSYA, a yellow principle from the safflower, Carthamus tinctorius) has been proposed as a nontoxic alternative to other agents which reduce MPTP opening. We proposed that HSYA 1) prevents MPTP formation/opening in anoxic cardiac myocytes, and 2) protects the cells from morphologic changes seen during reoxygenation. We used cardiac myocytes in a plated-cell anoxia/reoxygenation protocol to examine the effect of both HSYA and cyclosporin A (CsA) on MPTP formation. Plated myocytes were subjected to anoxia/reoxygenation, stained with calcein and MitoTracker Red, and examined for MPTP opening by confocal microscopy. Rod-shaped cells very rarely showed an open MPTP in this system; by contrast, hypercontracted (round) cells showed MPTP mostly “open”. However, a significant number of round cells showed MPTP in the closed configuration. Neither HSYA nor CsA was effective in protecting the myocytes from anoxic damage. When ionomycin (a known activator of MPTP) was used in place of anoxia, both CsA and HSYA were effective in keeping the MPTP in the closed configuration. Therefore, HSYA can prevent MPTP formation, but the multiplicity of events which cause myocyte damage during anoxia may limit its cardioprotective potential.