Pathogenesis of Heart Disease and Targets for Gene Therapy

Myocardial ischemia associated with CAD is the primary cause of myocardial failure (60). Systemic hypertension, disorders of lipid metabolism, and diabetes are the predominant predisposing factors for CAD (2). Acute ischemic events, if sufficiently prolonged, will lead to irreversible damage and infarction, underlined by alterations in membrane fluidity, intracellular hydrogen ion concentration and metabolic activity, and eventual cell death, resulting in arrhythmia and impaired pump function...

Using Rat Models for Understanding the Genetic Basis of Blood Pressure Regulation

Blood pressure (BP) in humans and rodents is well-recognized as a quantitative trait (i.e., variable from low to high) under polygenic control (i.e., controlled by many genes) (4). High BP (hypertension) is an undesirable trait because it is a major risk factor for cardiovascular and renal diseases. The expected result from finding and characterizing the genes that control BP is the gaining of insights into the etiology of hypertension. Several of the complications (such as those listed in the...

The Angiotensin Ii Receptors

The RAS is a major physiological regulator of body fluid volume, electrolyte balance, and arterial pressure. Originally, the RAS was viewed solely as an endocrine system angiotensinogen of hepatic origin is secreted into the systemic circulation and cleaved to Ang I by renin (in its active form as found in blood plasma), and then by both plasma and endothelial membrane-bound ACE to produce the active octapeptide Ang II. Increasing evidence suggests that other complete RAS may reside within...

Genetic Influences on Pharmacodynamics

As highlighted above, there are some interesting examples of cardiovascular drugs whose pharmacokinetics are affected by genetic variation, leading to differences in efficacy or toxicity. However, it seems that genetic variability in the proteins involved in drug pharmacodynamics will ultimately be more informative to understanding response variability for cardiovascular drugs. Unlike drug metabolism pharmacogenomics, for which there are nearly five decades of research, drug target...

How Pharmacogenomics Might Be Used Clinically

Pharmacological management of cardiovascular diseases is largely based on evidence from clinical trials and guidelines from expert consensus panels. For example, current consensus guidelines recommend the institution of angiotensin-converting enzyme (ACE) inhibitors and -blockers and consideration of spironolactone in all patients with severe heart failure, based on evidence that these drugs reduced morbidity and mortality in several large clinical trials (1). However, not all participants...

Pharmacogenomic Considerations On Ang Ii Receptors

The response of patients to antihypertensive therapy is variable individuals may respond differently to different medications, suggesting that treatment should be matched to individual responsiveness. The two main targets in RAS for an antihypertensive therapy are ACE and AT-1, with ACE inhibitors and AT-1 antagonists (or blockers), respectively. Then, polymorphisms in ACE and ATjR genes may have influence on the antihypertensive response after, of course, ACE inhibitor or AT-1 blocker...

Genes In Causal Pathway Of Disease Cholesteryl Ester Transfer Protein Polymorphism

The presence of a polymorphism in the cholesteryl ester transfer protein (CETP) gene (which is also called Taq1B) is associated with alterations in lipoprotein levels and high-density lipoprotein (HDL) concentrations. The CETP enzyme has a central role in reverse cholesterol transport (RCT), whereby cholesterol from peripheral tissues is transported back to the liver, where it is preferentially excreted into bile. There are several proteins crucial for RCT. These proteins include the...

Somatic Gene Delivery Of Tissue Kallikrein In Hypertensive Animal Models

One strategy to study the potential role of kallikrein kinin in hypertension is via protein or gene delivery. Oral administration of purified pig pancreatic kallikrein has been used to temporarily lower the blood pressure of hypertensive patients (32,33). This hypotensive effect requires repeated administrations of the enzyme, and the antihypertensive effect disappears shortly after the treatment is discontinued (32,33). Somatic gene delivery results in continuous expression of the gene of...

The Tissue Kallikreinkinin System Components

Tissue kallikreins (E.C. 3.4.21.35) belong to a subgroup of serine proteinases that process kininogen substrates and release vasoactive kinin peptides (1). The well-recognized function of tissue kallikrein is mediated by lysyl-bradykinin (Lys-BK or kallidin) and bradykinin (BK), which consist of 10 and 9 amino acid peptides, respectively. Kinins are then degraded by enzymes, such as kininases I and II and neutral endopeptidase to produce a number of kinin metabolites or inactive fragments....

Tissue Kallikrein In Hypertension

A dominant gene expressed as renal or urinary kallikrein may be associated with a reduced risk of hypertension (16). This finding suggests that high urinary kallikrein may have a protective effect against the development of high blood pressure. Reduced urinary kallikrein excretion has also been described in a number of genetically hypertensive rat models such as spontaneously hypertensive rats (SHR), New Zealand rats, Fawn-Hooded rats, and Dahl salt-sensitive (DSS) hypertensive rats (1721)....

Hypertension

Primary systemic hypertension is a chronic elevation of blood pressure that is thought to be the result of interplay between polygenic and numerous environmental factors. Hypertension is a well established risk factor for secondary conditions, such as stroke, atherosclerosis, peripheral vascular disease, cardiac failure, and others (1). Although current pharmacological interventions are able to offer effective blood pressure control, such treatments are relatively short-acting, have a...

Association Of The 217a Variant Of Agt Gene With Hypertension

Because hypertension is more common in African-American subjects, our laboratory is interested in understanding molecular mechanisms involved in hypertension in the African-American population. We have therefore analyzed 186 African-American and 127 Caucasian subjects with hypertension (mean age 59 10 yr) and 156 African-American and 135 Caucasian normotensive controls (mean age 58 10 yr). All of these subjects were recruited from the outpatient department of The State University of New York...

Genomewide Analysis To Identify Hypertensionrelated Genes

Krushkal et al. (3) performed a genome-wide linkage analysis of systolic BP on 427 sibling pairs and identified four regions of the human genome that show statistical significant linkage. These regions are on chromosomes 2, 5, 6, and 15. These chromosomal regions include numerous potential candidates, such as phospholamban, estrogen receptor (ER), aminopeptidase N, a lB-adrenergic receptor, dopamine receptor type 1A (DR-1A), calmodulin, and sodium-calcium exchanger. However, none of these genes...

M235t Polymorphism Of Agt Gene And Hypertension

The AGT gene contains five exons and four introns, which span 13 kb (18). An extensive study of the potential role of the AGT gene in human essential hypertension was performed on two large series of hypertensive siblingships yielding 379 sibling pairs. The highly polymorphic CA dinucleotide repeat marker located in the 3'-region of the AGT gene and the powerful affected sibling pair methodology were used to obtain evidence of a genetic linkage between the AGT gene and hypertension in this...

Targeting of Adenoviral Vectors

Gene Therapy

The process of infection of the Ad5 serotype has been well documented see Fig. 1 , and occurs as a two-stage process. In the first phase, attachment to the host cell occurs via an interaction between the knob domain of the capsid fiber and the Coxsackie-adenovirus receptor CAR 46,47 . Following this, internalization occurs via the activation of avP3 or avp5 integrins by the penton base of the adenoviral capsid 48,49 . Dechecchi et al. showed that Ad5 binding could be inhibited by the presence...

General Properties of AVV and LVV

AVV and LVV are very different in respect to their genomic organization, structure, and life cycle. Whereas AVV vectors are descendants of the widespread pathogens associated with mild human infections of the respiratory tract and eyes, LVV vectors have been derived from either a deadly human immunodeficiency virus HIV or a feline immunodeficiency virus FIV . From the practical point of view, the most important features of any viral gene delivery system include its safety in use i.e.,...

Introduction

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

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....

Titin and ZDisc Proteins aactinin2 Mlp Zaspcypher TCap Telethonin

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

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...

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...

Gene Therapy to Treat Myocardial Ischemic Disease Using Therapeutic Angiogenesis

Gene Therapy And Myocardial Ischemia

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 ....

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...

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...