Expressional and functional regulation of nitric oxide synthases in hypertensive cardiomyopathy
(2003)
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- Authors
- Supervisors
- Balligand, Jean-Luc
- Abstract
- In this work, we continued to the understanding of the expressional and functional regulation of the nitric oxide synthases (NOS) in nonfailing hypertensive hypertrophic cardiomyopathy. There is now considerable evidence that NO production and/or NO bioavailability is impered in hypertensive hypertrophic cardiomyopathy. However, the cause of this impairment and the pathophysiologic role of this abnormality remain unclear. The latter prompted us to test the hypothesis that myocardial dysfunction in hypertrophic heart is due to alteration of myocardial NO/NOS bioactivity or signalling. For this purpose, we chose two animal models of nonfailing, hypertensive cardiomyopathy : 1. dog model with hypertrophic cardiomyopathy induced by perinephrinic hypertension (PHT dog), and 2. rat genetic model of arterial hypertension and hypertension-induced myocardial hypertrophy (Spontaneously Hypertensive Rat, SHR). Both models of hypertensive cardiomyopathy were tested at two stages of development of the disease (i.e., PHT dog at 3 and 7 weeks of age ; and SHR at 18 and 63 weeks of age), compared to age-matched control animal. Using immunohistochemical approaches, we demonstrated the reduction of expression of endothelial NOS (eNOS) and their inhibitory regulators, such as caveolin-1 and caveolin-3, in extracts from left ventricvle (LV) of both PHT dog and adult SHR models. In addition, in the extracts from LV subendocardium of PHT dogs and in the whole extracts from LV of SHR, we found increased levels of Hsp90, a chaperone protein known to promote eNOS and neuronal NOS (nNOS) activation. We also show a marked increase of nNOS proteins in the LV of older SHR, wich had not been described before. No signal for inducible NOS (iNOS) was detectable bu Western blot from the same hearts of both models. Moreover, we found that, in 7-week PHT dogs, the expressional changes are accompanied by a time-dependent impairment of coronary endothelial function and altered diastolic relaxation. Despite reduced eNOS abundance, we found a marked sensitivity to NOS inhibitors in 7-week PHT dogs (reflected by an increase in systemic vascular resistance and a significant alteration of dialostic function after in vivo infusion of NOS inhibitor, L-NAME). This paradox may be explained by parallel downregulation of caveolin-1 and caveolin-3 and upregulation of Hsp 90 that potentiate residual NOS activity. We also found that, in SHR, changes in NOS abundance are not necessarily correlated with concurrent changes in tissue cGMP levels, but they are associated with increased production of superoxide anions.In conclusion, the simple measurement of NOS abundance does not allow to predict the enzyme's activity in vivo ; our study emphasizes the need for paradellel measurement of expressional changes of allosteric regulators of NOS, i.e. caveolin-1, caveolin-3 and Hsp 90, to predict the enzyme's activity and sensitivity to pharmacologic inhibitors. The coordinated expressional changes in eNOS (and nNOS) and their allosteric regulators may be viewed as a compensatory mechanism to maintain the production of bioactive NO (even in the face of increased oxidant stress).
- Affiliations
UCLouvain MD/MED/MINT/FATH - Laboratoire de pharmacothérapie
Citations
Piech, A. R. (2003). Expressional and functional regulation of nitric oxide synthases in hypertensive cardiomyopathy. https://hdl.handle.net/2078.5/110797