Showing papers by "Dipak K. Das published in 2003"

Molecular mechanisms of cardioprotection by a novel grape seed proanthocyanidin extract.

Abstract: Free radicals and oxidative stress play a crucial role in the pathophysiology of a broad spectrum of cardiovascular diseases including congestive heart failure, valvular heart disease, cardiomyopathy, hypertrophy, atherosclerosis and ischemic heart disease. We have demonstrated that IH636 grape seed proanthocyanidin extract (GSPE) provides superior antioxidant efficacy as compared to Vitamins C, E and beta-carotene. A series of studies were conducted using GSPE to demonstrate its cardioprotective ability in animals and humans. GSPE supplementation improved cardiac functional assessment including post-ischemic left ventricular function, reduced myocardial infarct size, reduced ventricular fibrillation (VF) and tachycardia, decreased the amount of reactive oxygen species (ROS) as detected by ESR spectroscopy and reduced malondialdehyde (MDA) formation in the heart perfusate. Cardiomyocyte apoptosis detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) staining. In concert, the proapoptotic signals mediated by JNK-l and c-fos proteins were also reduced suggesting that the novel cardioprotective properties of GSPE may be at least partially attributed to its ability to block anti-death signaling mediated through the proapoptotic transcription factors and genes such as JNK-1 and c-JUN. In a separate study, GSPE pretreatment significantly inhibited doxorubicin-induced cardiotoxicity as demonstrated by reduced serum creatine kinase (CK) activity, DNA damage and histopathological changes in the cardiac tissue of mice. Concentration-dependent efficacy of GSPE was also assessed in a hamster atherosclerosis model. Approximately 49 and 63% reduction in foam cells, a biomarker of early stage atherosclerosis, were observed following supplementation of 50 and 100 mg GSPE/kg body weight, respectively. A human clinical trial was conducted on hypercholesterolemic subjects. GSPE supplementation significantly reduced oxidized LDL, a biomarker of cardiovascular diseases. Finally, a cDNA microarray study demonstrated significant inhibition of inducible endothelial CD36 expression, a novel cardioregulatory gene, by GSPE. These results demonstrate that GSPE may serve as a potential therapeutic tool in promoting cardiovascular health via a number of novel mechanisms.

STAT signaling in ischemic heart: a role of STAT5A in ischemic preconditioning.

Abstract: We recently demonstrated that ischemic preconditioning (PC) induced by cyclic episodes of short duration of ischemia and reperfusion potentiates a signal transduction cascade involving Janus kinase...

HFE Mutation and Dietary Iron Content Interact to Increase Ischemia/Reperfusion Injury of the Heart in Mice

Abstract: Hereditary hemochromatosis is an inherited pathological condition characterized by iron overload in several vital organs including heart. To increase our understanding of the underlying pathogenic mechanisms of hereditary hemochromatosis, we used a HFE gene knockout mouse model that replicates hereditary hemochromatosis. A group of mice with no copies of HFE gene and corresponding wild-type mice were maintained either on low-iron (30 ppm) or high-iron (300 ppm) diet since birth. The results of our study revealed that HFE gene knockout mouse hearts were susceptible to ischemia-reperfusion injury as evidenced by increased postischemic ventricular dysfunction, increased myocardial infarct size and cardiomyocyte apoptosis compared with wild-type control hearts. The degree of injury increased in the hearts of the mice fed high-iron diet. The hearts of the HFE knockout mice showed increased iron deposition, increased content of reactive oxygen species (ROS) as evidenced by the increased formation of malondialdehyde, and reduced antioxidant enzymes including superoxide dismutase, catalase, and glutathione peroxidase. The results suggest that increased amount of ROS and reduced antioxidant reserve secondary to iron overloading may be instrumental for the susceptibility of the HFE gene knockout mice to cardiac injury.

Effects of L-carnitine and its derivatives on postischemic cardiac function, ventricular fibrillation and necrotic and apoptotic cardiomyocyte death in isolated rat hearts

Abstract: The study aimed to examine whether L-carnitine and its derivatives, acetyl-L-carnitine and propionyl-L-carnitine, were equally effective and able to improve postischemic cardiac function, reduce the incidence of reperfusion-induced ventricular fibrillation, infarct size, and apoptotic cell death in ischemic/reperfused isolated rat hearts. There are several studies indicating that L-carnitine, a naturally occurring amino acid and an essential cofactor, can improve mechanical function and substrate metabolism not only in hypertrophied or failing myocardium but also in ischemic/reperfused hearts. The effects of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine, on the recovery of heart function, incidence of reperfusion-induced ventricular fibrillation (VF), infarct size, and apoptotic cell death after 30 min ischemia followed by 120 min reperfusion were studied in isolated working rat hearts. Hearts were perfused with various concentrations of L-carnitine (0.5 and 5 mM), acetyl-L-carnitine (0.5 and 5 mM), and propionyl-L-carnitine (0.05, 0.5, and 5 mM), respectively, for 10 min before the induction of ischemia. Postischemic recovery of CF, AF, and LVDP was significantly improved in all groups perfused with 5 mM of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine. Significant postischemic ventricular recovery was noticed in the hearts perfused with 0.5 mM of propionyl-L-carnitine, but not with the same concentration of L-carnitine or L-acetyl carnitine. The incidence of reperfusion VF was reduced from its control value of 90 to 10% (p < 0.05) in hearts perfused with 5 mM of propionyl-L-carnitine only. Other doses of various carnitines failed to reduce the incidence of VF. The protection in CF, AF, LVDP, and VF reflected in a reduction in infarct size and apoptotic cell death in hearts treated with various concentrations of carnitine derivatives. The difference between effectiveness of various carnitines on the recovery of postischemic myocardium may be explained by different membrane permeability properties of carnitine and its derivatives.

Cardioprotection With High-Density Lipoproteins: Fact or Fiction?

Abstract: Epidemiological studies strongly suggest an inverse correlation between plasma high-density lipoprotein (HDL) concentration and the risk of ischemic heart disease.1,2 Experimental evidence also exists to indicate cardioprotective effects of HDL.3 However, the mechanism for protective effect of HDL against ischemic heart disease is not completely understood. Although the widely accepted mechanism comprises the ability of HDL to enhance reverse cholesterol transport,4 cholesterol-independent mechanisms have also been postulated. For example, lower HDL is associated with endothelial cell injury, which is involved both in the progression of atherogenesis and myocardial ischemia-reperfusion injury. The ability of HDL to inhibit endothelial adhesion molecule expression5 and to potentiate prostacyclin release from the endothelial cells6 further supports cholesterol-independent mechanism of HDL. Antiatherogenic property of HDL is mediated by its ability to release cholesterol from lipid-containing cells followed by esterification through lecithin:cholesterol acyltransferase and delivery to the liver and to steroidogenic organs for subsequent synthesis of bile acids and lipoproteins.7 Most importantly, HDL can inhibit oxidation of low-density lipoprotein (LDL) as well as the atherogenic effects of oxidized LDL by virtue of its antioxidant property. Atherosclerosis is an inflammatory disease characterized by adhesion of circulating monocytes to activated endothelial cells followed by migration to the subendothelium with the help of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin.8 Consistent with these reports, there is an increased expression of adhesion molecules in atherosclerotic plaque9 and upregulation of adhesion molecules in the acute thrombotic process. …

Ischemic Preconditioning and Apoptosis in Myocardial Ischemia

Abstract: An emerging body of evidence has now been accumulated to indicate the existance of a highly organized type of cell death, apoptosis, in the pathogenesis of a variety of cardiovascular diseases (30, 84). This process of cell death is a fundamentally important biological process that involves cell proliferation and differentiation to control tissue and organ homeostasis. Apoptotic cell death may be an integral part of the pathogenesis of cardiac dysfunction which is related to cardiac abnormalities associated with congestive heart failure, cardiomyopathy and other ischemic heart diseases. Myocardial infarction induces cell death by two different mechanisms: necrosis and apoptosis (2). The important distinguishing features of cell necrosis are rupture of cell membrane, cell swelling, plasma membrane breakdown, clumping of nuclear chromatin, swelling and disruption of sarcoplasmic reticulam and mitochondria and appearance of the granular densities in the matrix of mitochondria. Due to this rupture of the sarcoplasmic reticulam in the necrotic cardiocytes, calcium overloading takes place which causes disturbances in other electrolytes (28). On the other hand, apoptosis occurs in the absence of membrane rupture, and is characterized by internucleosomal cleavage of DNA by a Ca2+ and Mg2+ dependent endonuclease. Ultrastructural features of apoptosis include segregation of nuclear chromatin and condensation of the cytoplasm. Apoptotic cell surface develops protuberances which are known as apoptotic bodies, generally engulfed or digested by adjacent cells. Thus, apoptosis is an active, highly regulated, energy-requiring process while necrosis is a passive process and occurs in response to lethal injury.