The Future of Hypertension Therapy: Sense, Antisense, or Nonsense?

Abstract

Abstract-Hypertension is a debilitating disease with significant socioeconomic and emotional impact. Despite recent success in the development of traditional pharmacotherapy for the management of hypertension, the incidence of this disease is on the rise and has reached epidemic proportions by all estimates. This has led many to conclude that traditional pharmacotherapy has reached an intellectual plateau, and novel approaches for the treatment and control of hypertension must be explored. We have begun to investigate the possibility of treating and/or curing hypertension by using genetic means. In this review, we will provide evidence in favor of targeting of the renin-angiotensin system by antisense gene therapy as an effective strategy for the lifelong prevention of hypertension in the spontaneously hypertensive rat model. In addition, we will discuss the properties of an ideal vector for the systemic delivery of genes and the potential experimental hurdles that must be overcome to take this innovative approach to the next level of evaluation.

Potential of Gene Therapy Strategy for the Treatment of Hypertension

“…1 These observations have led many to propose that an increase in ACE2 would be beneficial for the cardiovascular system, whereas its deficiency may lead to cardiovascular pathophysiologies and hypertension. The following evidence additionally support this contention: (1) ACE2 gene maps to a defined QTL associated with hypertension in rat models; 38 (2) two SNPs in the ACE2 gene are shown to be associated with human coronary artery disease; 38 (3) Ang (1-7), a major product of ACE2, acts as a vasodilator, ACEi, and a possible inhibitor of the AT 1 R; 39 -41 (4) both ACE2 and its major product, Ang (1)(2)(3)(4)(5)(6)(7), are demonstrated to oppose proliferative and profibrotic effects of Ang II; [42][43][44] (5) disruption of the ACE2 gene in mouse results in an elevation of Ang II, impaired cardiac contractility, and induction of hypoxia-responsive genes in cardiac tissue; and (6) transgenic mice overexpressing ACE2 exhibit lower BP, whereas the decrease in ACE2 has been demonstrated in several animal models of hypertension. 38 A recent review from our group provides detailed conceptual support for the potential role of ACE2 as a novel therapeutic target for hypertension and CVDs.…”

“…[1][2][3] In the knockdown approach, genes that have been implicated in the elevation of BP and cardiovascular pathophysiology (particularly members of the renin-angiotensin system [RAS]) are targeted with the anticipation of decreasing their transcription and translation. With the overexpression approach, genes that are relevant in reducing high blood pressure (BP), such as kallikrein, atrial natriuretic peptide (ANP), endothelial nitric oxide synthase (eNOS), and heme oxygenase, are overexpressed.…”

“…This concept is not restricted to the SHR and has now been proven to be successful with the use of both genetic and nongenetic animal models of hypertension. [11][12][13][14][15] In addition, the targeting of other genes linked to high BP and hypertension produce similar antihypertensive effects, most notably angiotensinogen, 16,17 ␤-adrenergic receptor, 18,19 and epidermal growth factor receptor. 20,21 Taken together, these observations establish that AS targeting is effective in the prevention of hypertension.…”

Similar effects on rat renal mesangial cells by expressing different fragments of adrenomedullin gene in vitro1

“…Currently, both non-viral and viral vectors are used to express the heterogeneous genes, each of them with their own advantages and disadvantages. The advantages of non-viral vectors are: (i) non-vial vectors do not integrate the heterogeneous genes into recipient-cell genome, therefore it is considered safe for researchers and will have higher clinical acceptability; (ii) there are minimal or no immune effects, and none of the safety concerns regarding infection is found with viral vectors [21] ; (iii) manipulate and delivery of plasmids into cells is much easier; and (iv) although plasmid-delivered DNA does not integrate into the recipient-cell genome, delivery of plasmids in vivo can maintain very prolonged effects [22] . In the present study, we chose plasmid pEGFP-N3 as the vector.…”

Multilocus effects of the renin–angiotensin–aldosterone system genes on blood pressure response to a thiazide diuretic

“…4 In addition, BP response to a diuretic differs with race and gender, with African-Americans and women having greater BP responses than their non-Hispanic White and male counterparts. 5 Drug therapies that target the renin-angiotensin-aldosterone (RAA) system have proven useful in HTN control, 6 and, because of that, the system has been the subject of genetic studies of BP and HTN. 7 The RAA system regulates BP levels and fluid and electrolyte balance through multiple actions of angiotensin II, a potent vasoconstrictor hormone that also enhances renal tubular sodium reabsorption through direct and indirect (via aldosterone) effects on proximal and distal nephron segments, respectively.…”