Objectives-Increasing HDL levels is a potential strategy for the treatment of atherosclerosis. Methods and Results-ITX5061, a molecule initially characterized as a p38 MAPK inhibitor, increased HDL-C levels by 20% in a human population of hypertriglyceridemic subjects with low HDL levels. ITX5061 also moderately increased apoA-I but did not affect VLDL/LDL cholesterol or plasma triglyceride concentrations. ITX5061 increased HDL-C in WT and human apoA-I transgenic mice, and kinetic experiments showed that ITX5061 decreased the fractional catabolic rate of HDL-CE and reduced its hepatic uptake. In transfected cells, ITX5061 inhibited SR-BI-dependent uptake of HDL-CE. Moreover, ITX5061 failed to increase HDL-C levels in SR-BI Ϫ/Ϫ mice. To assess effects on atherosclerosis, ITX5061 was given to atherogenic diet-fed Ldlr ϩ/Ϫ mice with or without CETP expression for 18 weeks. In both the control and CETP-expressing groups, ITX5061-treated mice displayed reductions of early atherosclerotic lesions in the aortic arch Ϫ40%, PϽ0.05), and a nonsignificant trend to reduced lesion area in the proximal aorta. Conclusions-Our data indicate that ITX5061 increases HDL-C levels by inhibition of SR-BI activity. This suggests that pharmacological inhibition of SR-BI has the potential to raise HDL-C and apoA-I levels without adverse effects on VLDL/LDL cholesterol levels in humans. Key Words: scavenger receptor B-I Ⅲ high-density lipoproteins Ⅲ inhibitors Ⅲ p38 MAPK Ⅲ atherosclerosis P lasma high-density lipoprotein (HDL) levels are inversely correlated with atherosclerotic cardiovascular disease, and raising HDL levels by lifestyle changes or pharmacological interventions is an emerging strategy that might help to reduce the residual burden of disease in patients treated with low-density lipoprotein (LDL)-lowering approaches. 1,2 Whereas increasing synthesis or infusion of apolipoprotein A-I (apoA-I) or HDL reduces atherosclerosis in animals and humans, it is not clear that all approaches to raising HDL will reduce atherosclerosis.The scavenger receptor B-I (SR-BI) is a major factor regulating HDL catabolism. SR-BI binds HDL and mediates the selective uptake of HDL-cholesteryl ester (CE) in the liver and steroidogenic tissues. 3 Although the role of SR-BI in HDL metabolism in mice and rats has been clearly shown, much less information is available on the function of SR-BI in humans. Primary human hepatocytes do demonstrate selective uptake of HDL-CE, 4 but the quantitative importance of this pathway has not been shown. In humans, cholesteryl ester transfer protein (CETP), a factor lacking in mice and rats, plays a major role in HDL-CE catabolism. In the present study, we demonstrate that ITX5061, a molecule initially characterized as a p38 mitogen-activated protein kinase (MAPK) inhibitor, caused an increase in HDL cholesterol (HDL-C) and apoA-I levels in humans. Studies in mice and cultured cells indicated that ITX5061 is an inhibitor of the SR-BI activity. Interestingly, ITX5061 did not cause increases in very-low-density lipopr...
SUMMARY We studied the morphologic and histologic characteristics of redundant prolapsing ("myxomatous") mitral valves from 12 symptomatic patients with severe mitral regurgitation who required mitral valve replacement and compared our findings with those in 13 control valves.The mean surface area of the "myxomatous" mitral valves (MMVs)
SUMMARY To better define the mechanisms of blood pressure control in states of catecholamine excess, we infused norepinephrine for 28 days using subcutaneously implanted osmotic pumps in dogs previously instrumented for monitoring left ventricular dynamics and cardiac output. Plasma norepinephrine rose from 238 ± 27 to 4346 ± 952 pg/ml at 21 days, while epinephrine and dopamine levels did not change. Heart rate fell from 85 ± 4 to 63 ± 6 beats/min, while arterial pressure was unchanged from baseline. Total peripheral resistance rose 0.011 ± 0.003 mm Hg/ml/min from a control value of 0.029 ± 0.002 mm Hg/ml/min, and cardiac output decreased 1093 ± 292 ml/min from a baseline level of 3575 ± 156 ml/min. Since stroke volume did not change, the maintenance of arterial pressure is related to decreases in cardiac output secondary to bradycardia. Buffering mechanisms are responsible for maintenance of systemic arterial pressure because hexamethonium and atropine caused hypertension. Although left ventricular end-diastolic pressure, end-diastolic diameter, shortening, rate of change of pressure, velocity of myocardial shortening, cardiac work, stroke work, and the double product did not change significantly during the study, postmortem examination demonstrated biventricular hypertrophy. Thus, despite markedly elevated catecholamine levels and no elevation of systemic arterial pressure, myocardial hypertrophy developed. These studies lend support to the hypothesis that norepinephrine may be a direct myocardial tropic hormone and suggest that intense activation of reflex buffering mechanisms maintains blood pressure in the normal range during chronic catecholamine infusion. (Hypertension 9: 582-590, 1987) KEY WORDS • bradycardia • hypertension • hypertrophy • catecholamines • total peripheral resistance • atropine E LEVATIONS in catecholamine levels may be associated with a number of disease states, including mitral valve prolapse (MVP), 1 -2 chronic myocardial failure, 3 " 6 and pheochromocytoma. 7 These disease states may be characterized by sustained or episodic hypertension, myocardial dysfunction, and cardiomyopathy.Recently, it has been noted that certain patients with MVP, chronic myocardial failure, or pheochromocytoma have dysautonomia, manifested by abnormalities in heart rate or blood pressure response (or both) to orthostatic change or exercise. 8 " 12 Some investigations of patients with MVP having dysautonomia are consistent with evidence of hyperadrenergic states and some with simultaneous hypervagatonia. 9 -13 Significant elevations in serum catecholamine levels have been observed in a group of symptomatic patients with MVP 1 ' l4 ; these results have been confirmed by other workers. 2 ' 8> l5 Patients with chronic myocardial failure, regardless of etiology, have elevated plasma norepinephrine (NE) levels. 16 In addition, defects in baroreceptor reflex-mediated vasoconstrictor responses have been noted in dogs 17 and in patients 18 -19 with marked myocardial dysfunction.Several studies, summarized by Ec...
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