Mevalonate availability and cardiovascular functions.

Abstract

Data delineating the relationship between disorders of cholesterol metabolism and elevated blood pressure (BP) do not exist. We postulated that mevalonate, the metabolic precursor of endogenous cholesterol and the direct product of 3-hydroxy-3-methylglutaryl-CoA reductase, was a contributing factor for the maintenance of vascular tone and systemic BP. We conducted in vivo, ex vivo, and in vitro experiments in normotensive and hypertensive rats, where exogenous mevalonate and lovastatin, a competitive inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase, were used, respectively, to increase or limit mevalonate availability. Mevalonate decreased BP in the whole animal without significant change in plasma cholesterol. Incubation of aortas with mevalonate attenuated their reactivity to norepinephrine and increased their response to endothelium-dependent and -independent relaxing factors. Lovastatin, in contrast, had the opposite effect in vivo and in vitro: it increased BP, enhanced vascular response to norepinephrine, and impaired endothelium-dependent and -independent relaxations. terol (circulating or accumulating in cell membrane) and BP control.Cell cholesterol homeostasis is dependent not only on exogenous availability of the sterol but also on endogenous synthesis. Intracellular cholesterol synthesis is part of a very tightly regulated system (the mevalonate pathway) that satisfies the cell requirement not only for cholesterol but also for various nonsterol (isoprenoid) products such as dolichol, ubiquinone, and prenylated proteins. The participation of these nonsterol metabolites in vascular physiology and BP regulation is essentially unknown. However, indications that they might play a major role can be inferred from published work (9-11). In the mevalonate pathway, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase is a critical rate-limiting step (12), ensuring adequate supply of mevalonate for sterol and nonsterol synthesis. Modulation of mevalonate production and cellular availability can be achieved with competitive inhibitors of the enzyme, such as lovastatin. The drug, which has been utilized extensively to study the regulation of cholesterol synthesis, has recently been used to elucidate the existence of covalent isoprenylation of cellular proteins and the functional role of protein prenylation. In in vitro studies exploring the functional impact of blocking HMG-CoA reductase activity with lovastatin, the specificity of action of lovastatin has been tested by the ability of mevalonate to restore normal cell function.Considering the absence of a direct relationship between plasma cholesterol and BP and the potential role of endogenous cholesterol and nonsterol isoprenoids in vascular physiology, we postulated that mevalonate availability directly influences vascular functions and, ultimately, BP. The hypothesis was tested in vivo, ex vivo, and in vitro using the rat as a standard laboratory model ofarterial pressure regulation. METHODSIn Vivo Experiments. Normotensive Wistar Kyoto (WK...

Mevalonate availability affects human and rat resistance vessel function.

“…A similar impact of lovastatin was observed previously by us in vivo and in vitro (9). Our experiments cannot clearly separate the effect of lovastatin on the endothelium from that on the smooth muscle since the response to SNP was also impaired.…”

“…In our earlier study (9), lovastatin appeared to act on several pathways including NE-induced contraction and acetylcholine and sodium nitroprusside (SNP)-induced relaxation. It is known that stimulation of membrane receptors, such as the adrenergic and muscarinic receptors, triggers the elevation of 1.…”

Farnesyl analogues inhibit vasoconstriction in animal and human arteries.

“…In two recent studies (6, 7), we observed that systemic blood pressure and vascular tone were dependent on the metabolic availability of mevalonate, an early precursor of cholesterol. Reduction of mevalonate availability with lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) 1 reductase inhibitor, enhanced the response of conductance and resistance vessels to vasoconstrictors, impaired vasodilation, and raised arterial pressure (6). Increased mevalonate availability with exogenous mevalonate had opposite effects and normalized the reactivity of vessels exposed to lovastatin in vitro.…”

Farnesol Inhibits L-type Ca2+ Channels in Vascular Smooth Muscle Cells

“…However, a direct effect on PKC is unlikely as farnesol does not affect PKC cellular localization in cell lines derived from normal tissue (12). Other studies have reported the existence of a farnesol-specific, orphan nuclear receptor in vertebrate cells, the farnesoid X-activated receptor, but the role of this receptor in cell signaling pathways still needs to be defined (13,14).We have shown that mevalonate (MVA) availability is an important determinant of vascular tone in animal and human arteries (15,16). Decreased vascular MVA availability following treatment with lovastatin, a 3-hydroxy-3-methylglutarylCoA reductase inhibitor, was associated with an increase in the response to vasoconstrictors, whereas addition of MVA to the arteries inhibited vasoconstriction.…”

“…We have shown that mevalonate (MVA) availability is an important determinant of vascular tone in animal and human arteries (15,16). Decreased vascular MVA availability following treatment with lovastatin, a 3-hydroxy-3-methylglutarylCoA reductase inhibitor, was associated with an increase in the response to vasoconstrictors, whereas addition of MVA to the arteries inhibited vasoconstriction.…”