Approach may lead to long-term direct gene regulation; Next tests: heart failure, heart attack
BETHESDA, Md. (Nov. 30, 2004) – Using a novel vector delivery system researchers at the University of Florida designed a "nifty, seemingly simple idea" that turned out to produce significant results in terms of preventing enlargement and hardening of the heart associated with hypertension.
The study goes a long way in learning how hypertension develops as well how genes can be targeted and regulated within specific organs. Because the procedure didn't simultaneously reduce blood pressure, the approach could also have therapeutic application in treating heart failure and heart attacks, according to a paper in Physiological Genomics, published online by the American Physiological Society.
The clinical importance of hypertension was highlighted by Dr. Claude Lenfant, former director of the National Heart, Lung, and Blood Institute (NHLBI), when he announced the latest report on hypertension last year. Lenfant said: "Americans' lifetime risk of developing hypertension is much greater than we'd thought. For instance, those who do not have hypertension at age 55 have a 90% risk of going on to develop the condition."
The current Florida study started with a straightforward goal: "to determine whether the angiotensin II type 2 receptor (AT2R) influences cardiac hypertrophy (enlargement) and myocardial and perivascular fibrosis." The results were quite striking, according to the laboratory leader, Dr. Mohan K. Raizada: "The procedure prevented the heart from enlarging and prevented thickening of the ventricular walls. It also prevented the formation of fibrosis – an extracellular matrix like collagen -- that makes it harder for the heart to pump."
Without AT2R protection, left ventricular wall thickness (LVWT) increased 123% and the heart weight to body weight ratio (measuring overall "enlargement") rose 129%. At the same time, myocardial fibrosis rose 300% and perivascular fibrosis rose 158%.
AT2R protection sharply reduces most hypertensive indicators
However, when protected by AT2R through cardiac transduction LVWT was 85% lower, HW/BW was 91% and myocardial fibrosis was 43% lower after a two-week infusion of angiotensin II (AT2), which induced hypertension.
These marked effects of AT2R may have clinical importance for hypertension and other cardiovascular diseases as well methodological implications for gene and cellular therapies of all sorts.
Lead author Beverly L. Falcón notes that the research used "normal" rats so that the beneficial outcomes to the heart were totally due to the AT2R procedure rather than any possible inherent genetic influences. Thus, "this present model is physiologically more relevant …to human disease because cardiac hypertrophy is dependent on the RAS (renin-angiotensin system) without the confounding genetic determinants associated with the SHR," or spontaneously hypertensive rat, used in other studies.
Lentiviral vector enables targeted delivery; 100% transduction not necessary
The study utilized a lentiviral vector to deliver and enable overexpression of AT2R in the heart on a long term basis. The paper notes that AT2R was predominantly overexpressed in the heart. Furthermore, "all of these effects were seen despite limited transduction of cardiac tissue." In addition, the authors note, "this present study demonstrates a significant level of AT2R expression in cardiac tissue, although the expression was not uniformly distributed throughout the tissue. "Despite this, we observed dramatic cardioprotective effects," they added.
Raizada said that "from a cell therapy viewpoint, this is fascinating that you don't need to transduce all the cardiac cells to observe global beneficial effects on the heart. In this case only 30-40% was transduced and it appears that this amount is sufficient. What this suggests is that there's some cellular communication among cardiac cells that 'tells' the rest of the heart to conform."
On the pathology level, Falcón said that while the AT2R prevented hypertrophy and fibrosis of the heart, the perivascular fibrosis (around peripheral blood vessels) was not reduced, nor was blood pressure. On a clinical level this may seem a negative result, but Raizada noted that "we were targeting the gene to only affect the heart, so not influencing blood pressure is a good thing. Even better, is that in heart failure, you may or not have high blood pressure present, so this is very good: to be able to affect the heart, without affecting the vasculature."
Next steps: The results and methodology of the study could lead in many directions, Falcón and Raizada agreed. Among them are:
- To confirm whether AT2R cardioprotective effects are at the local RAS level.
- To determine if AT2R is the right gene that will give the most beneficial effect, or if there are other candidates such as the recently identified ACE2, a gene that expresses beneficial peptides.
- To determine if AT2R provides cardioprotective effects against heart failure and/or myocardial infarction (heart attack).
- To see if the lentiviral vector system "can be used to drive AT2R expression with specific promoters, such as oxygen-sensitive response elements to investigate the role of this receptor in ischemia-induced heart damage."
- To try and find a system of controlling, at will, gene expression.
Source: Eurekalert & othersLast reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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