Gene Therapy to Treat Peripheral Arterial Disease Using Therapeutic Angiogenesis
Critical limb ischemia, which is estimated to develop in 500 to 1000 individuals per million per year, is considered one of most suitable diseases for gene therapy. In a large proportion of these patients, the anatomical extent and the distribution of arterial occlusive disease make the patients unsuitable for operative or percutaneous revascularization. Thus, the disease frequently follows an inexorable downhill course. Of importance, there is no optimal medical therapy for critical limb...
Chromosome 8
Several independent genetic linkage studies provide suggestive evidence for BP QTL on RNO8. These have been reviewed previously 5 . Two recent genetic linkage analyses using F2 S x SHR and F2 S x AS populations also indicate BP QTL on RNO8 52,60 . To date, very little progress has been made toward confirming and dissecting these BP QTL using substitution mapping. There has been one report of an SHR.Lx Lx BN.Lx Cub congenic strain that has successfully trapped a BP QTL in the region indicated in...
Introduction Mhr
In spite of recent advances in the treatment of hypertension, many patients fail to respond to standard therapies targeted mainly at regulating blood volume, electrolyte balance, and the peripheral renin-angiotensin system. In a recent review, S. J. Mann writes One such form of hypertension is the often overlooked entity of neurogenic hypertension. These implications underscore the need for further clinical and basic research attention concerning neurogenically mediated hypertension 1 . The...
References Brw
1. Glazier AM, Nadeau JH, Aitman TJ. Finding genes that underlie complex traits. Science 2002 298 2345-2349. 2. Glazier AM, Scott J, Aitman TJ. Molecular basis of the Cd36 chromosomal deletion underlying SHR defects in insulin action and fatty acid metabolism. Mamm Genome 2002 13 108-113. 3. Zhang Y, Leaves NI, Anderson GG, et al. Positional cloning of a quantitative trait locus on chromosome 13q14 that influences immunoglobulin E levels and asthma. Nat Genet 2003 18 18. 4. Luft FC....
Chromosome 3
BP QTL on RNO3 are reported by multiple genetic linkage analyses 17,19,50-55 . In 1999, Cicila et al. reported an S.R congenic strain that successfully trapped a BP QTL 19 . As shown in Fig. 2C, study 1, this QTL on RNO3 is located toward the distal end of RNO3. However, it is only recently that Palijan et al. 56 constructed and studied multiple S.LEW congenic strains spanning the proximal region of RNO3, and reported that the proximal region of RNO3 contains a BP QTL Fig. 2C, study 2 wherein...
Adenovirus 1
Adenovirus is a double-stranded DNA virus that can infect both dividing and nondivid-ing cells with high efficiency as it targets mammalian cells with specific membrane receptors. Viruses then enter the cells by receptor-mediated endocytosis and translocate into the nucleus. Most of the adenoviruses are episomal, and thus do not integrate into the host DNA. Because they are not integrated, the episomal DNA eventually becomes inactive or degraded, and the transgene will no longer be expressed....
Titin and ZDisc Proteins aactinin2 MLP ZASPCypher TCapTelethonin
Both thin filaments actin and thick filaments myosin through a titin anchor at Z-discs. Therefore, the Z-disc is considered a sensor of contraction with other Z-disc localizing proteins to keep the normal integrity of the cardiac muscle 9 . A giant protein, titin or connectin is the third most abundant protein of vertebrate striated muscle after myosin and actin 7,8 . The titin molecule is a flexible filament that is more than 1 m long, spanning half the sarcomere from the Z-disc amino terminus...
Conclusions Sco
In this review, we have discussed a number of polymorphisms which might interfere with the effectiveness of statin therapy. Most polymorphisms described in this chapter have an indirect effect on statin response. Only a few of them are in genes encoding for proteins that are involved in the disposition of statins, or in genes-encoding proteins that are direct targets of statin therapy. More proteins are involved in efficacy and metabolism of statins therefore, more genes are involved, and...
References Qzn
1. Deshmukh R, Smith A, Lilly LS. Hypertension. In Pathophysiology of heart disease. Lilly LS, ed. . 1998 Williams amp Wilkins, Baltimore, MD 267-288. 2. American Heart Association Heart Disease and Stroke Statistics, 2004. Update Dallas, TX American Heart Association, 2003. 3. Sowers, JR. Is hypertension an insulin-resistant state Metabolic changes associated with hypertension and antihypertensive therapy. Am Heart J 1991 122 932-935. 4. Ferrannini E, Natali A. Essential hypertension,...
References Nmf
1. Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins kallikreins, kininogens, and kininases. Pharmacol Rev 1992 44 1-80. 2. Marceau F. Kinin B1 receptors a review. Immunopharmacology 1995 30 1-26. 3. Regoli D, Gobeil F, Nguyen QT, et al. Bradykinin receptor types and B2 subtypes. Life Sci 1994 55 735-749. 4. Regoli D, Rhaleb, NE, Drapeau G, Dion S. Kinin receptor subtypes. J Cardiovasc Pharmacol 1990 15 S30-S38. 5. Chao J, Tillman DM, Wang MY, Margolius HS, Chao L. Identification of a...
Advantage Of Gene Therapy Over Conventional Pharmacotherapy
Despite a large arsenal of therapeutic agents, conventional pharmacological therapy has not cured hypertension and, in fact, does not control the disease in the majority of patients. Possible reasons for poor control of BP include incorrect targets of therapy, and poor education, economics, availability of health care, follow-up care, drug availability, and compliance. Even if the ideal drug was available for each patient, it is more likely that compliance would be the major factor in...
Liver AGT
As mentioned previously, the liver is considered the primary site of AGT synthesis and the main source of plasma AGT. We therefore examined the effects of hepatic AGT elimination on the circulating pool of AGT. To knock out AGT specifically in the liver, Fig. 2. Schematic of Cre-loxP System. The targeted gene is designed with loxP sites flanking one or more important coding exons filled boxes . The addition of Cre-recombinase will result in the deletion of the flanked exon, disabling the gene....
Frequency of the Genetic Mutations in Familial and Sporadic DCM
Although the prevalence of mutations in DCM described previously will be influenced by the patient population, several studies show that the causes of DCM are heterogenetic. Defects in 8-sarcoglycan were found in two among 50 young DCM patients aged 3 d-18 yr 61 , and two among 52 DCM patients mean aged 50, age 11-71 yr in Finnish patients. In the later study, the desmin gene and the metavinculin-specific exon of the vinculin gene were also examined in the same group, but no mutations were...
References Xrc
1. Reid IA, Morris BJ, Ganong WF. The renin-angiotensin system. Annu Rev Physiol 1978 40 377-410. 2. Campbell DJ. Circulating and tissue angiotensin systems. J Clin Invest 1987 79 1-6. 3. Schmidt-Ott KM, Kagiyama S, Phillips MI. The multiple actions of angiotensin II in atherosclerosis. Regul Pept 2000 93 65-77. 4. Gomez RA, Norwood VF. Developmental consequences of the renin-angiotensin system. Am J Kidney Dis 1995 26 409-431. 5. Bader M, Peters J, Baltatu O, Muller DN, Luft FC, Ganten D....
Snp In Atr Gene
Polymorphisms genetic variations of high frequency may be the result of variations in the DNA sequence, such as the change of only one nucleotide single nucleotide polymorphism SNP , or an insertion or deletion of one to several hundred bases resulting from the DNA recombination failures, or insertion deletion of DNA repeating sequences, such as tandem repeat sequences, microsatellites, or AluI sequences. The human AT1R gene has a length of greater than 55 kb and is composed of five exons and...
Genes Identified As Responsible For Idiopathic Dcm
The genes that cause familial DCM are summarized in Table 1 according to their intracellular localization Z-disc localizing proteins a-actinin-2, muscle LIM protein MLP , Z-disc alternatively spliced PDZ motif ZASP cypher, titin-cap T-cap telethonin costameres, adherens junctions, desmosomes, and interemediate filaments vinculin metavinculin, desmoplakin, plakoglobin, desmin, lamin A C, a-actinin-2, MLP, dystrophin, 5-sarcoglycan sarcomere proteins cardiac a-actin, -myosin heavy chain, cardiac...
Desmosome Adherens Junction Costamere and Interemediate Filaments
In the heart, cell-cell and cell-substrate interactions are mediated by specific structures desmosome, adherens junction, and costamere Fig. 2A,B . These structures are important for holding cells together under the influences of the extracellular matrix and for their development, migration, proliferation, shape, and function. Desmosomal cell-cell junctions are found predominantly in the heart and skin. In the heart, desmosomes are localized at the intercalated disc. They link the...
Gene Therapy to Treat Myocardial Ischemic Disease Using Therapeutic Angiogenesis
Similar ideas have been applied to treat coronary artery disease. A human gene therapy trial to treat coronary artery disease using VEGF165 gene has been started by Professor Isner and colleagues 21,22 . His group performed intramuscular injection of naked plasmid encoding VEGF gene into ischemic myocardium through mini-operation. Similar to human trials in PAD, transfection of VEGF gene resulted in a marked increase in blood flow and improved clinical symptoms without apparent toxicity 21 ....
Gene Therapy vs Pharmacotherapy
Gene Therapy for Cardiovascular Disease Using Oligonucleotide-Based Stategy Perspectives in Gene Therapy References Recent progress in molecular and cellular biology has developed numerous effective cardiovascular drugs. However, there are still number of diseases for which no known effective therapy exists, such as peripheral arterial disease, ischemic heart disease, restenosis after angioplasty, vascular bypass graft occlusion, and transplant coronary vasculopathy. Currently, gene therapy is...
Structures Of The Cardiac Cytoskeleton Cell Adhesion And The Sarcomere
The major function of cardiomyocytes is in the cardiac contraction-relaxation cycle. The contractile proteins in cardiomyocytes constitute about 75 of the total volume of the myocardium, although only about one-third of the number of all the cells in the myocardium are cardiomyocytes. About half of each ventricular cell is occupied by myofibers, and about one-fourth to one-third by mitochondria. The major proteins involved in contraction and relaxation are the thin filament composed of actin,...
Chromosome 5
Garrett and Rapp 30 have developed and tested multiple S.LEW congenic strains on RNO5 and concluded that there are two closely linked interactive BP QTL on RNO5 Fig. 2D, studies 1 and 2 . The QTL was found to be interactive because strains with congenic segments that contained only QTL1 or QTL2 did not show a BP effect, but strains with congenic segments that contained both QTL did show a significant BP effect. BP QTL on RNO5 has also been localized using a SHR.BN congenic strain Fig. 2D, study...
Role Of Agt In Hypertension
The RAS plays an important role in the regulation of BP. The octapeptide, angiotensin II Ang II , is one of the most active vasopressor agents and is obtained by the proteolytic cleavage of a larger precursor molecule, angiotensinogen AGT , which is primarily synthesized in the liver and to a lesser extent in the kidney, brain, heart, adrenal, fat, and vascular walls. The human AGT cDNA is 1455 nucleotides long and codes for a 485-amino acid protein 9 . AGT is first converted by renin to...
Adipose Tissue AGT
Until recently, adipose tissue was considered exclusively as a body energy store without other function. However, the realization that adipocytes can produce many peptides and hormones including leptin, atrial natriuretic peptide, and AGT has led us to view this tissue as an endocrine secretory organ with consequences on the cardiovascular system 51 . For instance, AGT produced by the adipose tissue may act locally to affect adipocyte growth and differentiation, or may be secreted into the...
Gene Therapy for Myocardial Hypertrophy and Remodeling
The progression of HF resulting from hemodynamic overload, chronic myocardial ischemia, or acute MI is invariably accompanied by hypertrophy and remodelling of the left ventricle 100 . This process, which usually begins as an adaptive physiological mechanism aimed at normalizing wall stress in response to the increased load or myocyte death from infarction, eventually becomes maladaptive, resulting in alteration in ventricular geometry, mechanical decompensation, and contractile failure....
References Bvn
1. Heilmann C, von Samson P, Schlegel K, et al. Comparison of protein with DNA therapy for chronic myocardial ischemia using fibroblast growth factor-2. Eur J Cardiothorac Surg 2002 22 957-964. 2. Isner JM, Pieczek A, Schainfeld R, et al. Clinical evidence of angiogenesis after arterial gene transfer of phVEGF165 in patient with ischaemic limb. Lancet 1996 348 370-374. 3. Baumgartner I, Pieczek A, Manor O, et al. Constitutive expression of phVEGF165 after intramuscular gene transfer promotes...
References Qbi
1. Braunwald E, Zipes DP, Libby P, eds. Heart disease a textbook of cardiovascular medicine. 6th ed. W.B. Saunders, Philadelphia 2001. 2. Cohn JN, Bristow MR, Chien KR, et al. Report of the National Heart, Lung, and Blood Institute Special Emphasis Panel on Heart Failure Research. Circulation 1997 95 766-770. 3. Chien KR. Stress pathways and heart failure. Cell 1999 98 555-558. 4. Hein S, Kostin S, Heling A, Maeno Y, Schaper J. The role of the cytoskeleton in heart failure. Cardiovasc Res 2000...
Atr Gene Polymorphisms And Hypertension
Hypertension has a multifactorial etiology with a strong genetic component. Of many human candidate gene loci examined, those encoding components of the RAS are considered to be among the most plausible candidates. The association of renin gene polymorphism with essential hypertension has been scarcely reported 16 . On the contrary, several studies have demonstrated a link between the angiotensinogen AG gene and hypertension 17-19 , particularly the M235T variant which correlates with both...
Atr Gene Polymorphism And Atherosclerosisrelated Diseases
Coronary artery disease CAD is a major public health problem in industrialized countries. Dyslipidemia, arterial hypertension, and diabetes mellitus, the main risk factors for CAD apart tobacco consumption, are influenced by both environmental and genetic factors. Several studies have suggested that the activation of the RAS could be an important contributor to CAD. The best-documented of associations between the occurrence of CAD and polymorphisms in genes RAS component is the I D polymorphism...