gkt137831 and Hypertension

Hypertension is associated with oxidative stress and perivascular inflammation, critical contributors to perivascular fibrosis and accelerated vascular ageing. Oxidative stress can promote vascular inflammation, creating options for potential use of NADPH oxidase inhibitors in pharmacological targeting of perivascular inflammation and its consequences. Accordingly, we characterized age-related changes in oxidative stress and immune cell infiltration in normotensive (WKY) and spontaneously hypertensive rats (SHRs). Subsequently, we used pharmacological inhibitors of Nox1 (ML171) and Nox1/Nox4 (GKT137831; 60 mg/kg), to modulate NADPH oxidase activity at the early stage of spontaneous hypertension and investigated their effects on perivascular inflammation and fibrosis. RESULTS: Ageing was associated with a progressive increase of blood pressure as well as an elevation of the total number of leukocytes, macrophages and NK cells infiltrating perivascular adipose tissue (PVAT) in SHRs but not in WKY. At 1 month of age, when blood pressure was not yet different, only perivascular NK cells were significantly higher in SHR. Spontaneous hypertension was also accompanied by the higher perivascular T cell accumulation, although this increase was age independent. Aortic Nox1 and Nox2 mRNA expression increased with age only in SHR but not in WKY, while age-related increase of Nox4 mRNA in the vessels has been observed in both groups, it was more pronounced in SHRs. At early stage of hypertension (3-months) the most pronounced differences were observed in Nox1 and Nox4. Surprisingly, GKT137831, dual inhibitor of Nox1/4, therapy increased both blood pressure and perivascular macrophage infiltration. Mechanistically, this was linked to increased expression of proinflammatory chemokines expression (CCL2 and CCL5) in PVAT. This inflammatory response translated to increased perivascular fibrosis. This effect was likely Nox4 dependent as the Nox1 inhibitor ML171 did not affect the development of spontaneous hypertension, perivascular macrophage accumulation, chemokine expression nor adventitial collagen deposition. In summary, spontaneous hypertension promotes ageing-associated perivascular inflammation which is exacerbated by Nox4 but not Nox1 pharmacological inhibition.

Topics: Adipose Tissue; Age Factors; Animals; Aorta; Blood Pressure; Disease Models, Animal; Enzyme Inhibitors; Fibrosis; Hypertension; Inflammation Mediators; Killer Cells, Natural; Macrophages; Male; NADPH Oxidase 1; NADPH Oxidase 4; Pyrazolones; Pyridones; Rats, Inbred SHR; Rats, Inbred WKY; Signal Transduction; T-Lymphocytes; Vasculitis

NADPH oxidases (Noxs) 1/4 dual inhibitor GKT137831 prevents hypertensive cardiac remodelling in angiotensin II-infused transgenic mice with cardiomyocyte-specific human Nox4 (c-hNo x 4 Tg); however, further research is still required to determine the beneficial role of GKT137831 in hypertensive cardiac remodelling in other types of hypertensive models because this hypertensive model is insufficient to mimic the complicated pathological mechanisms of hypertension. A disintegrin and metalloprotease 17 (ADAM17) promotes the shedding of tumour necrosis factor α (TNF-α), TNF-α receptor, interleukin 1 receptor-II and interleukin 6 (IL-6) receptor from cells, thereby mediating the signalling pathways induced by corresponding proinflammatory cytokines. This study aimed to determine whether GKT137831 prevents hypertensive cardiac remodelling and its mechanisms of action in the rats with abdominal artery coarctation (AAC). The rats subjected to AAC were orally given GKT137831 for a consecutive period of 28 days. Echocardiography and histological analysis were performed to evaluate cardiac remodelling; and immunohistochemistry and real-time PCR were used to detect the expression of proinflammatory cytokines. GKT137831 significantly suppressed hypertensive cardiac remodelling in AAC-induced hypertensive rats. Concurrently, Nox1/4 dual inhibitor GKT137831 reduced the protein and mRNA levels of proinflammatory cytokines interleukin 1β (IL-1β), IL-6, and TNF-α in the left ventricle of AAC-induced hypertensive rats. Moreover, the treatment with GKT137831 markedly diminished the protein and mRNA levels of ADAM17 in the left ventricle of AAC-induced hypertensive rats. In summary, Nox1/4 dual inhibitor GKT137831 protects against hypertensive cardiac remodelling in AAC-induced hypertensive rats, and the inhibition of ADAM17-dependent proinflammatory cytokines-induced signalling pathways are related to its beneficial effect on hypertensive cardiac remodelling.

Topics: ADAM17 Protein; Animals; Arteries; Constriction; Cytokines; Hypertension; Inflammation; Male; Myocytes, Cardiac; NADPH Oxidase 1; NADPH Oxidase 4; Pyrazoles; Pyrazolones; Pyridines; Pyridones; Rats; Rats, Sprague-Dawley; Signal Transduction