BMPRII influences the response of pulmonary microvascular endothelial cells to inflammatory mediators.

Mutations in the bone morphogenetic protein receptor (BMPR2) gene have been observed in 70 % of patients with heritable pulmonary arterial hypertension (HPAH) and in 11-40 % with idiopathic PAH (IPAH). However, carriers of a BMPR2 mutation have only 20 % risk of developing PAH. Since inflammatory mediators are increased and predict survival in PAH, they could act as a second hit inducing the development of pulmonary hypertension in BMPR2 mutation carriers. Our specific aim was to determine whether inflammatory mediators could contribute to pulmonary vascular cell dysfunction in PAH patients with and without a BMPR2 mutation. Pulmonary microvascular endothelial cells (PMEC) and arterial smooth muscle cells (PASMC) were isolated from lung parenchyma of transplanted PAH patients, carriers of a BMPR2 mutation or not, and from lobectomy patients or lung donors. The effects of CRP and TNFα on mitogenic activity, adhesiveness capacity, and expression of adhesion molecules were investigated in PMECs and PASMCs. PMECs from BMPR2 mutation carriers induced an increase in PASMC mitogenic activity; moreover, endothelin-1 secretion by PMECs from carriers was higher than by PMECs from non-carriers. Recruitment of monocytes by PMECs isolated from carriers was higher compared to PMECs from non-carriers and from controls, with an elevated ICAM-1 expression. CRP increased adhesion of monocytes to PMECs in carriers and non-carriers, and TNFα only in carriers. PMEC from BMPR2 mutation carriers have enhanced adhesiveness for monocytes in response to inflammatory mediators, suggesting that BMPR2 mutation could generate susceptibility to an inflammatory insult in PAH.

NF-κB pathway is involved in CRP-induced effects on pulmonary arterial endothelial cells in chronic thromboembolic pulmonary hypertension.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by thrombofibrotic obstruction of proximal pulmonary arteries. The cellular and molecular mechanisms underlying the pathogenesis remain incompletely understood, although we recently evidenced the potential involvement of the inflammatory marker C-reactive protein (CRP). We aimed to investigate the intracellular mechanisms induced by CRP in proximal pulmonary arterial endothelial cells (PAEC). PAEC were isolated from vascular material obtained during pulmonary endarterectomy. RNA was extracted from CRP-stimulated PAEC, and first-stand cDNA was generated. A RT(2) profiler PCR Array was used to evaluate the expression of 84 key genes related to NF-κB-mediated signal transduction. CRP-induced NF-κB activation was studied. The effects of pyrrolidine-dithio-carbamate ammonium (PDTC), an inhibitor of the NF-κB pathway, were investigated on CRP-induced adhesion of monocytes to PAEC, adhesion molecule expression, endothelin-1 (ET-1), interleukin-6 (IL-6), and von Willebrand factor (vWF) secretion. Compared with nonstimulated PAEC, serotonin receptor 2B was downregulated by 25%, inhibitor of NF-κB kinase subunit epsilon (IKBKE) by 30%, and toll-like receptor-4 and -6 by 18 and 39%, respectively, in CRP-stimulated PAEC. The transcription factor FOS was threefold upregulated. CRP induced RelA/NF-κBp65 phosphorylation. PDTC dose dependently inhibited the adhesion of monocytes to CRP-stimulated PAEC. PDTC also inhibited the CRP-induced expression of ICAM-1 at the surface of PAEC. PDTC impaired the secretion of ET-1 by 18% and tended to inhibit the secretion of IL-6 by CRP-stimulated PAEC by 46%. PDTC did not inhibit the CRP-induced secretion of vWF. These results suggest an involvement of the NF-κB pathway in mediating different effects of CRP on proximal CTEPH-PAEC.

Contribution of circulating angiotensinogen concentrations to variations in aldosterone and blood pressure in a group of African ancestry depends on salt intake.

In high-Na(+), low-K(+) diets, which suppress renin release in salt-sensitive groups, the mechanisms maintaining increases in renin-angiotensin-aldosterone system activation downstream from renin and renin-angiotensin-aldosterone system-induced effects on blood pressure (BP) are uncertain. Whether circulating angiotensinogen concentrations (AGT) or its determinants may contribute to maintaining serum aldosterone concentrations (aldosterone) and increases in BP on high-Na(+), low-K(+) diets was evaluated in 579 participants of a community sample of African ancestry. Plasma renin concentrations were inversely related to BP (P<0.0001) and an index of salt intake (24-hour urinary Na(+)/K(+), P<0.0001). An interaction between AGT and urinary Na(+)/K(+) was independently associated with aldosterone (P<0.001) and systolic BP (SBP; P<0.05). Independent of confounders, in participants with urinary Na(+)/K(+) at or more than the median for the sample, AGT was positively associated with aldosterone (P<0.0001) and SBP (P<0.005). No independent AGT-aldosterone or AGT-SBP relationships were noted in participants with urinary Na(+)/K(+) less than the median for the sample. Standardized ß-coefficients (slopes) of AGT-aldosterone and AGT-SBP relationships were greater in participants with urinary Na(+)/K(+) at or more than the median (AGT-aldosterone=0.30±0.06, AGT-SBP=0.16±0.05) compared with those with urinary Na(+)/K(+) less than the median (AGT-aldosterone=-0.04±0.06; AGT-SBP=-0.03±0.05; P<0.01-0.0001 for comparison of slopes). The AGT-SBP relationship in participants with urinary Na(+)/K(+) at or more than the median for the sample was equivalent to the relationship between body mass index and BP. In conclusion, in participants of African ancestry, in the presence of high-Na(+), low-K(+) diets, which suppress renin release, renin-angiotensin-aldosterone system activation and its impact on BP are maintained in part by AGT.

Relationship of predominantly mild current smoking to out-of-office blood pressure in a community sample in Africa.

OBJECTIVES: As the impact of mild smoking on blood pressure (BP) is uncertain, we assessed the relationship between predominantly mild current smoking and out-of-office BP and the effect of angiotensin-converting enzyme (ACE) genotype on this relationship in a community sample of black African ancestry. METHODS: In 689 participants randomly recruited from an urban, developing community of black African descent, we assessed smoking habits, out-of-office (24-h), and in-office conventional and central (applanation tonometry) BP, and ACE insertion (I)/deletion (D) variant genotype. RESULTS: A total of 14.5% (n=100) were current smokers, the majority being mild (72%, 7.4 ± 4.6 cigarettes/day). Despite current smokers having only modest increases in in-office (P<0.05) and similar central aortic BP values as nonsmokers, current smokers had higher unadjusted (P<0.005-P<0.0005) and multivariate adjusted 24-h SBP/DBP (mmHg; smokers=123 ± 15/76 ± 10; nonsmokers=118 ± 14/72 ± 9; P<0.005-P<0.0005) than nonsmokers, effects that were DD genotype-dependent (P<0.005 for interaction) and replicated in sex-specific groups, nondrinkers, and in overweight and obese. Current smoking was second only to age in the quantitative impact on 24-h DBP. Smoking 4.6 cigarettes per day (one standard deviation) translated into increases in 24-h SBP (mmHg) of 2.12 [confidence interval (CI)=1.77-2.47] in all participants and 3.62 (CI=3.13-4.12) in participants with the DD genotype. The risk of uncontrolled 24-h BP was increased in smokers as compared to nonsmokers (adjusted odds ratio=1.87, CI=1.02-3.41, P<0.05), an effect that was enhanced in participants with the DD genotype (adjusted odds ratio=4.01, CI=1.59-10.09, P<0.005). CONCLUSION: Mild current smoking is independently associated with an appreciable proportion of out-of-office BP in a black African community, an effect that is ACE genotype-dependent.

Dietary-induced obesity hastens the progression from concentric cardiac hypertrophy to pump dysfunction in spontaneously hypertensive rats.

We explored whether dietary-induced obesity hastens the transition from concentric left ventricular (LV) hypertrophy to pump dysfunction in spontaneously hypertensive rats (SHRs) and the mechanisms thereof. After feeding rats a diet for 4 to 5 months, obesity was induced in SHRs and Wistar-Kyoto (WKY) control rats. Obesity was not associated with abnormal blood glucose control (glycosylated hemoglobin) or with increases in systolic blood pressure. However, in SHRs, but not in WKY rats, obesity was associated with a reduced LV chamber systolic function, as determined by echocardiography, and in isolated perfused heart studies. A marked increase in LV end diastolic diameter and a right shift in the LV diastolic pressure-volume relation were noted in obese SHRs but not in obese WKY rats. Moreover, LV intrinsic myocardial systolic function, as determined from the slope of the linearized LV systolic stress-strain relationship (LV myocardial end systolic elastance), was markedly reduced in obese as compared with lean SHRs, whereas LV myocardial end systolic elastance was maintained in obese WKY rats. Obesity increased LV weight, cardiomyocyte width, cardiomyocyte apoptosis (TUNEL), the activity of myocardial matrix metalloproteinases (zymography), and serum leptin concentrations in SHRs but not in WKY rats. In conclusion, SHRs are susceptible to the adverse effects of dietary-induced obesity on the heart, an effect that hastens the progression from concentric LV hypertrophy to pump dysfunction independent of blood pressure changes or alterations in glycosylated hemoglobin. This effect may be mediated through a proclivity of SHRs to developing both obesity-induced effects on cardiomyocyte apoptosis and activation of myocardial collagenases through leptin resistance and obesity-induced hypertrophy.