Author : Persoulla Nicolaou
Publisher :
ISBN 13 :
Total Pages : 239 pages
Book Rating : 4.:/5 (32 download)
Book Synopsis The Role of Inhibitor-1 and Heat Shock Protein 20 in Cardiac Pathophysiology by : Persoulla Nicolaou
Download or read book The Role of Inhibitor-1 and Heat Shock Protein 20 in Cardiac Pathophysiology written by Persoulla Nicolaou and published by . This book was released on 2008 with total page 239 pages. Available in PDF, EPUB and Kindle. Book excerpt: Cardiovascular disease, which remains the leading cause of mortality in the Western world, is manifested in contractile dysfunction, myocardial infarction and arrhythmias. These detrimental effects are partially attributed to impaired Ca cycling and cell death. Since calsequestrin (CSQ) and inhibitor-1 (I-1) are key regulators of Ca cycling and the anti-apoptotic small heat shock protein 20 (Hsp20) is an important mediator of cardioprotection, this dissertation sought to gain further insights into the role of these proteins in cardiac pathophysiology. CSQ is a crucial regulator of Ca load in the sarcoplasmic reticulum and the Ca-release channel, the ryanodine receptor. Interestingly, human CSQ null mutations have been associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). To further address the significance of CSQ and CSQ null mutations, this dissertation attempted to generate a mouse model with ablation of CSQ. I-1 and its phosphorylation at Thr35 are important mediators of the heart's beta-adrenergic responses. To address any potential beneficial effects of enhanced I-1 activity in the adult heart, a mouse model with inducible expression of active I-1 (T35D) was generated. Active I-1 expression significantly enhanced contractility, associated with preferential phospholamban (PLN) and myosin light chain 2a phosphorylation. Upon ischemia/reperfusion (I/R), active I-1 augmented contractile function, associated with increased pThr17-PLN phosphorylation. Further examination revealed that the infarct region and apoptotic as well as necrotic injury were significantly attenuated by enhanced I-1 activity, associated with suppression of the endoplasmic reticulum stress response. These findings indicate that active I-1 may represent a potential therapeutic strategy in myocardial infarction. Hsp20 and its phosphorylation at Ser16 protect cardiomyocytes against apoptosis. To determine whether genetic variants exist in human Hsp20, which may modify these beneficial effects, the Hsp20 gene was sequenced in dilated cardiomyopathic patients and individuals with no heart disease. A C59T substitution was identified in Hsp20 in one patient and three individuals without heart disease. This mutation changes a conserved proline residue into leucine at position 20 (P20L), resulting in secondary structural alterations. The significance of this variant was assessed by subjecting cardiomyocytes, infected with Ad. GFP, Ad. WT-Hsp20 and Ad. P20L-Hsp20, to simulated ischemia/reperfusion. Expression of WT-Hsp20 significantly attenuated apoptotic injury, while the P20L-Hsp20 mutant showed no protection. This was associated with the mutant's diminished phosphorylation at Ser16. Furthermore, stimulation of cardiomyocytes with isoproterenol and protein kinase A-dependent phosphorylation in vitro confirmed the impaired ability of the mutant Hsp20 to become phosphorylated at Ser16. These findings indicate that the P20L substitution in Hsp20, may adversely affect the ability of human carriers to cope with cellular stress. Furthermore, a C29T transversion was identified exclusively in black cardiomyopathic males. This mutation results in substitution of serine at position 10 to phenylalanine (S10F), with similar structural alterations to the P20L mutant, suggesting that the S10F substitution may also have adverse effects on Hsp20's cardioprotective properties. Collectively, this dissertation provides novel insights into the role of these key regulatory proteins in the diseased myocardium, further illuminating the molecular and genetic defects, associated with cardiovascular disease, which may provide potential therapeutic strategies to alleviate its detriment.
