Article

Targeting the vasoprotective axis of the renin-angiotensin system: a novel strategic approach to pulmonary hypertensive therapy.

Department of Physiology and Functional Genomics, College of Medicine, University of Florida, PO Box 100274, Gainesville, FL 32610, USA.
Current Hypertension Reports (Impact Factor: 3.9). 08/2010; 12(4):212-9. DOI: 10.1007/s11906-010-0122-6
Source: PubMed

ABSTRACT A decade has passed since the discovery of angiotensin-converting enzyme 2 (ACE2), a component of the ACE2-angiotensin (Ang)-(1-7)-Mas counterregulatory axis of the renin angiotensin system (RAS). ACE2 is considered an endogenous regulator of the vasoconstrictive, proliferative, fibrotic, and proinflammatory effects of the ACE-Ang II-angiotensin II type 1 receptor (AT(1)R) axis. Both animal and clinical studies have emerged to define a role for ACE2 in pulmonary arterial hypertension (PAH). There is scientific evidence supporting the concept that ACE2 maintains the RAS balance and plays a protective role in PAH. The activation of pulmonary ACE2 could influence the pathogenesis of PAH and serve as a novel therapeutic target in PAH. Current therapeutic strategies and interventions have limited success, and PAH remains a fatal disease. Thus, more research that establishes the novel therapeutic potential and defines the mechanism of the ACE2-Ang-(1-7)-Mas counterregulatory axis in PAH is needed.

0 Bookmarks
 · 
39 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although echocardiography-derived tricuspid regurgitant jet velocity (TRV) is associated with increased mortality in sickle cell disease (SCD), its rate of increase and predictive markers of its progression are unknown. We evaluated 55 subjects (median age: 38 years, range: 20-65 years) with at least two measurable TRVs, followed for a median of 4·5 years (range: 1·0-10·5 years) in a single-centre, prospective study. Thirty-one subjects (56%) showed an increase in TRV, while 24 subjects (44%) showed no change or a decrease in TRV. A linear mixed effects model indicated an overall rate of increase in the TRV of 0·02 m/s per year (P = 0·023). The model showed that treatment with hydroxycarbamide was associated with an initial TRV that was 0·20 m/s lower than no such treatment (P = 0·033), while treatment with angiotensin converting enzyme inhibitors and angiotensin receptor blockers was associated with an increase in the TRV (P = 0·006). In summary, although some patients have clinically meaningful increases, the overall rate of TRV increase is slow. Treatment with hydroxycarbamide may decrease the progression of TRV. Additional studies are required to determine the optimal frequency of screening echocardiography and the effect of therapeutic interventions on the progression of TRV in SCD.
    British Journal of Haematology 07/2013; · 4.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Pulmonary arterial hypertension (PAH) is associated with refractory vasoconstriction and impaired NO-mediated vasodilatation of the pulmonary vasculature. Vascular tone is regulated by light chain (LC) phosphorylation of both nonmuscle (NM) and smooth muscle (SM) myosin, which are determined by the activities of MLC kinase and MLC phosphatase. Further, NO mediated vasodilatation requires the expression of a leucine zipper positive (LZ+) isoform of the myosin targeting subunit (MYPT1) of MLC phosphatase. The objective of this study was to define contractile protein expression in the pulmonary arterial vasculature and vascular reactivity in PAH. In severe PAH, compared to controls, relative LZ+MYPT1 expression was decreased (100±14% vs. 60±6%, p<0.05, n=7-8), and NM myosin expression was increased (15±4% vs. 53±5% of total myosin, p<0.05, n=4-6). These changes in contractile protein expression should alter vascular reactivity; following activation with Ang II, force activation and relaxation were slowed, and sustained force was increased. Further, the sensitivity to ACh-mediated relaxation was reduced. These results demonstrate that changes in the pulmonary arterial SM contractile protein expression may participate in the molecular mechanism producing both the resting vasoconstriction and the decreased sensitivity to NO-mediated vasodilatation associated with PAH.
    Journal of Molecular and Cellular Cardiology 10/2013; · 5.15 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We have previously demonstrated that diminazene aceturate (DIZE), a putative angiotensin 1-7 converting enzyme activator, protects rats from monocrotaline (MCT)-induced pulmonary hypertension (PH). The present study was conducted to determine if the beneficial effects of DIZE are associated with improvements in autonomic nervous system (ANS) modulation. PH was induced in male rats by a single subcutaneous injection of MCT (50mg/kg). A subset of MCT rats were treated with DIZE (15mg/kg/day) for a period of 21 days, after which the ANS modulation was evaluated by spectral and symbolic analysis of heart rate variability (HRV). MCT administration resulted in a significant (P<0.001) increase in the right ventricular systolic pressure (62±14mmHg) when compared with other experimental groups (Control: 26±6; MCT+DIZE: 31±7mmHg), while DIZE treatment was able to decrease this pressure. Furthermore MCT-treated rats had significantly reduced total power of HRV than the controls. On the other hand, although not significant, a trend towards increased HRV was observed in the MCT+DIZE group (Control: 108±47; MCT: 12±8.86 and MCT+DIZE: 40±14), suggesting an improvement of the cardiac autonomic modulation. This observation was further confirmed by the low-frequency/high-frequency index of spectral analysis (Control: 0.74±0.62; MCT: 1.45±0.78 and MCT+DIZE: 0.34±0.49) which showed that DIZE treatment was able to recover the ANS imbalance observed in the MCT-induced pulmonary hypertensive rats. Collectively, our results demonstrate that MCT-induced PH is associated with a significant increase in sympathetic modulation and a decrease in HRV, which are markedly improved by DIZE treatment.
    European journal of pharmacology 05/2013; · 2.59 Impact Factor

Full-text

View
0 Downloads
Available from