The Wnt/Frizzled pathway as a therapeutic target for cardiac hypertrophy: where do we stand?

Cardiac hypertrophy is an enlargement of the heart muscle in response to wall stress. This hypertrophic response often leads to heart failure. In recent years, several studies have shown the involvement of Wnt signalling in hypertrophic growth. In this review, the role of Wnt signalling and the possibilities for therapeutic interventions are discussed. In healthy adult heart tissue, Wnt signalling is very low. However, under pathological condition such as hypertension, Wnt signalling is activated. In recent years, it has become clear that both ß-catenin-dependent signalling and ß-catenin-independent signalling are involved in hypertrophic growth. Several studies, both in vitro and in vivo, have shown that genetic interventions in Wnt signalling at different levels resulted in an attenuated or diminished hypertrophic response. Therefore, inhibition of Wnt signalling could provide a new therapeutic strategy for cardiac hypertrophy, but further research on the Wnts and Frizzleds involved in the different forms of cardiac hypertrophy will be needed to achieve this goal.

Renal medullary effects of transient prehypertensive treatment in young spontaneously hypertensive rats.

AIM: Transient angiotensin II receptor blockade (ARB) leads to prolonged blood pressure (BP) lowering, but the underlying mechanism remains uncertain. Long-term BP control is regulated by the medullary microcirculation with the pericyte as contractile cell. We hypothesize that the prolonged BP effect is caused by increased medullary blood flow (MBF) associated with structural alterations based on reduced medullary pericyte number. METHODS: Four-week-old spontaneously hypertensive rats (SHR) were treated for 4 weeks with losartan (SHR-Los: 20 mg kg(-1) day(-1)), hydralazine (SHR-Hyd: 15 mg kg(-1) day(-1)), losartan and pan-caspase inhibitor zVAD (SHR-Los + 1 mg kg(-1) day(-1) zVAD), losartan and glycogen synthase kinase-3beta (GSK) inhibitor valproate (SHR-Los + 10 mg kg(-1) day(-1) Val) or placebo. BP, MBF and pericyte number were determined under and after treatment (8 and 12 weeks). Apoptotic pericytes were determined with alpha-actin and TUNEL double staining. Sodium concentration was determined in renal medulla and urine. RESULTS: Antihypertensive treatment equipotently reduced BP at 8 weeks of age. After drug withdrawal (12 weeks of age) BP reduction was restricted to SHR-Los (SHR-Los: 153 +/- 5, SHR-Hyd: 177 +/- 2, SHR: 184 +/- 3 mmHg). Simultaneously, MBF was increased and pericyte number reduced, while medullary and urinary sodium concentration increased. Transient ARB in combination with zVAD or valproate resulted in more medullary pericytes and higher BP (SHR-Los/zVAD: 164 +/- 7; SHR-Los/Val: 168 +/- 6 mmHg) compared with transient ARB alone. CONCLUSION: After drug withdrawal, transient ARB leads to increased MBF and is associated with a reduction in medullary pericytes. This may be associated with pericyte apoptosis as anti-apoptosis during transient ARB increases pericyte number and BP.

Changes in vascular distensibility during angiotensin-converting enzyme inhibition involve bradykinin type 2 receptors.

Changes in arterial stiffness and structure occur during cardiovascular diseases and can be modified by angiotensin-converting enzyme (ACE) inhibitors. In the present study we investigated the role of membrane-bound ACE (t-ACE) in the regulation of arterial structure and mechanics. Large and small arteries of t-ACE-/- mice were isolated to determine the passive pressure-diameter relationship. We observed that t-ACE-/- mice exhibit a reduced arterial distensibility compared to t-ACE+/+ mice. This reduced arterial distensibility was also observed after 9 weeks of captopril treatment (80 mg/kg/ day). We hypothesized that bradykinin type 2 receptor (BK(2)) stimulation might be involved in the regulation of arterial stiffness. t-ACE-/- and t-ACE+/+ mice were treated with Hoe 140 (1 mg/kg/day) for 14 days. After Hoe 140 treatment, both the structural and mechanical changes observed in the t-ACE-/- carotid artery were abolished. Although Hoe 140 administration increased blood pressure in both groups by approximately 10 mm Hg, the pressure difference between the two groups did not change. Thus, t-ACE is involved in the regulation of arterial distensibility. The changes observed in t-ACE-/- mice are not caused by an altered fetal development. Moreover, it is likely that the regulation of arterial distensibility by ACE involves stimulation of the BK(2) receptor.