Panax QuinquefoliumSaponin Attenuates Cardiomyocyte Apoptosis and Opening of the Mitochondrial Permeability Transition Pore in a Rat Model of Ischemia/Reperfusion

Abstract

Aims: Opening of the mitochondrial permeability transition pore (mPTP) is a critical event during ischemia/reperfusion (I/R) injury. Recently, we showed that Panax quinquefolium saponin (PQS) alleviates apoptosis of cardiomyocytes by suppressing excessive endoplasmic reticulum stress (ERS) during I/R injury. Here, we hypothesized that this anti-apoptotic effect might be mediated through inhibition of mPTP and the mitochondrial apoptotic pathway. Methods: Ninety-six healthy male Sprague-Dawley rats were randomly divided into sham, I/R, I/R+PQS (200 mg/kg/d), Cyclosporine A (CsA, 10 mg/kg), I/R+CsA (10 mg/kg), and I/R+PQS+CsA. I/R was modeled in rats by ligating the left anterior descending artery (LAD) for 30 min followed by 120 min of reperfusion. To evaluate the cardioprotective function of PQS, we measured hemodynamics, serum content of creatine kinase-MB (CK-MB), myocardial infarct size, and myocardial apoptotic index (AI). We investigated the underlying mechanism by examining changes in the mitochondrial ultrastructure and membrane potential (ΔΨm), dynamics of mPTP opening, expression of cleaved caspase-3, cleaved caspase-9 in the myocardium, Bcl-2 and Bax in the mitochondria versus cytosol, and translocation of cytochrome c. Results: Administration of PQS to I/R rats significantly reduced serum CK-MB level, infarct size and AI. In addition, PQS protected the mitochondrial structure, markedly inhibited mPTP opening and ΔΨm depolarization, led to upregulation of Bcl-2 and downregulation of Bax in the mitochondria compared to the cytosol, and suppressed the expression of cleaved caspase-9 and cleaved caspase-3, as well as I/R induced translocation of cytochrome c to the cytoplasm. Conclusion: Our results show that PQS can alleviate apoptosis of cardiomyocytes during I/R injury, possibly due to repressed mitochondrial apoptotic pathway associated with the opening of mPTP induced by myocardial I/R injury.

Morphine Postconditioning Protects against Reperfusion Injury via Inhibiting JNK/p38 MAPK and Mitochondrial Permeability Transition Pores Signaling Pathways

“…The opening of mPTP results in swelling of the mitochondrial matrix and rupture of the outer mitochondrial membrane, leading to the translocation of Cyt-c and other pro-apoptotic factors into the cytosol, and these actions rapidly produce cell death and apoptosis [18][19][20][21][22]. Because it appears to specifically open at the onset of reperfusion [17][18][19][20][21], mPTP has been strongly implicated as an end-effector in postC [23][24][25][26][27]. Previous studies demonstrated that MpostC modulates mitochondrial permeability transition pore (mPTP) opening via δ 1 opioid receptors [28] in isolated rat heart, but the post-receptor signaling mechanisms through which mPTP is regulated remain to be defined.…”

Andrographolide Attenuates LPS-Induced Cardiac Malfunctions Through Inhibition of IκB Phosphorylation and Apoptosis in Mice

“…Further studies will be needed to determine the potential mechanisms for inhibition of LPS-induced cardiomyocyte apoptosis by And; such studies should consider the opening of the mitochondrial permeability transition pore [39], stimulation of calcium-sensing receptors [40], and activation of cannabinoid type-2 receptors as possible mechanisms [41].…”

Pretreatment with low-dose gadolinium chloride attenuates myocardial ischemia/reperfusion injury in rats

“…Our study demonstrated that GdCl 3 administration reduced the number of TUNEL-positive cells, the death receptor expression, the cytochrome c release and the caspase-3 activation, suggesting an improved cell viability ( Figure 5). Previous studies have demonstrated the involvement of the mitochondrial and death receptor mediated pathways in cardiomyocyte apoptosis [13,14] . We investigated the regulators of apoptosis in intrinsic (mitochondria) and extrinsic (death receptor) pathways in isolated NRVMs to further elucidate the precise mechanism of GdCl 3 against myocardial injury.…”

“…Notably, cardiomyocyte apoptosis contributes to left ventricle dysfunction following cardiac surgery [12] . Previous studies have demonstrated that mitochondrial-related pathways and death receptor-mediated pathways are involved in I/Rinduced cardiomyocyte apoptosis [13][14][15] . Therefore, the exploration of the mechanisms of myocardial I/R-induced apoptosis and the identification of the potential target(s) to prevent or reverse cell apoptosis are important for the prevention and Several studies have suggested that a large concentration of arachidonic acid (AA) is released from cell membrane phospholipids under pathological conditions, such as stress, ischemia, hypoxia, and I/R, thus leading to multiple deleterious consequences, including abnormal excitation-contraction coupling due to alterations in ion channel kinetics, bioenergetic inefficiency, apoptosis, and accelerated necrosis, which collectively promote the development of heart dysfunction, heart failure, and sudden death [16,17] .…”