**15. Atherogenic manifestations and cyclic nucleotides**

Simultaneous and unilateral atherogenic modifications leading to accumulation of intracellu‐ lar lipids, enhanced proliferation, and hypersecretion of extracellular matrix point to a relationship between these processes. This relationship may occur at the level of cellular regulation, since all these processes are regulated by cyclic nucleotides, universal cellular regulators. It is well known that cyclic 3',5'-adenosine monophosphate (cAMP) inhibits cell proliferation, lipid synthesis and interactions between LDL and cell receptors, and synthesis and secretion of proteins (e.g., collagen and glycosaminoglycans) but stimulates hydrolisis of lipids. On the other hand, cyclic 3',5'guanosine monophosphate (cGMP) has opposite effects on these processes [94, 95].

It was found that cAMP content in atherosclerotic cells (cells populating atherosclerotic lesions) is two- to eight-fold lower than in normal intimal cells, while cGMP content in atherosclerotic cells is more than twofold higher than in normal cells [94, 96]. It was demon‐ strated that changes in the content of cyclic nucleotides are associated with altered activity of enzymes involved in their synthesis and degradation (cyclases and phosphodiesterases, respectively) [97]. For example, the activity of adenylate cyclase, an enzyme synthesizing cAMP, in fatty streak is lower than in uninvolved intima, being the lowest in atherosclerotic plaque. At the same time, the content of phosphodiesterase, an enzyme hydrolyzing cAMP, remains unchanged, which accounts for cAMP drop in atherosclerotic cells [97]. On the other hand, the activity of guanylate cyclase, an enzyme that synthesizes cGMP, is higher in fatty streak than in uninvolved intima, while the activity of phosphodiesterase is unchanged [97]. In atherosclerotic plaques, the situation is different: the activity of guanylate cyclase is the same as in uninvolved intima, while the activity of cGMP phosphodiesterase is much lower [97]. These changes clearly explain increased cGMP content in atherosclerotic lesions.

On the basis of numerous data, it can be stated that a decrease in the intracellular content of cAMP and an increase in that of cGMP in atherosclerotic lesions should lead to the stimulation of the main atherosclerotic manifestations at the cellular level, i.e., cell proliferation, lipid accumulation, and extracellular matrix production [95].

A question arises: what are the causes of the atherosclerosis-related changes in the intracellular contents of cyclic nucleotides? Upon incubation of human aorta intimal cells with modified LDL, a substantial lipid accumulation and parallel cAMP decrease and an increase of cGMP increase were observed, i.e., the exact changes in cyclic nucleotides occurring in atherosclerotic lesions (Table 2). It can be suggested that changes in the cyclic nucleotide system are caused by intracellular lipid accumulation.


The data are presented as percent of control (cells without LDL).

\*: Significant difference from the control, p<0.05.

As mentioned above, lipid accumulation affects the integrity of cellular network in human aortic intima. In the lipid-rich lesions, where the content of lipid-laden and foam cells is high, rupture of the network have been observed. It should be noted that cells not contacting with

A decrease in the rate of intracellular communication between cultured cells caused by modified LDL which induce intracellular lipid accumulation may account for the decreasing of cell contacts and their disruption. In fact, incubation of subendothelial intimal cells with modified LDL results in accumulation of intracellular lipids with a parallel reduction of the degree of intercellular communication [73]. It is reasonable to suggest that the reduction of cell‐

Simultaneous and unilateral atherogenic modifications leading to accumulation of intracellu‐ lar lipids, enhanced proliferation, and hypersecretion of extracellular matrix point to a relationship between these processes. This relationship may occur at the level of cellular regulation, since all these processes are regulated by cyclic nucleotides, universal cellular regulators. It is well known that cyclic 3',5'-adenosine monophosphate (cAMP) inhibits cell proliferation, lipid synthesis and interactions between LDL and cell receptors, and synthesis and secretion of proteins (e.g., collagen and glycosaminoglycans) but stimulates hydrolisis of lipids. On the other hand, cyclic 3',5'guanosine monophosphate (cGMP) has opposite effects

It was found that cAMP content in atherosclerotic cells (cells populating atherosclerotic lesions) is two- to eight-fold lower than in normal intimal cells, while cGMP content in atherosclerotic cells is more than twofold higher than in normal cells [94, 96]. It was demon‐ strated that changes in the content of cyclic nucleotides are associated with altered activity of enzymes involved in their synthesis and degradation (cyclases and phosphodiesterases, respectively) [97]. For example, the activity of adenylate cyclase, an enzyme synthesizing cAMP, in fatty streak is lower than in uninvolved intima, being the lowest in atherosclerotic plaque. At the same time, the content of phosphodiesterase, an enzyme hydrolyzing cAMP, remains unchanged, which accounts for cAMP drop in atherosclerotic cells [97]. On the other hand, the activity of guanylate cyclase, an enzyme that synthesizes cGMP, is higher in fatty streak than in uninvolved intima, while the activity of phosphodiesterase is unchanged [97]. In atherosclerotic plaques, the situation is different: the activity of guanylate cyclase is the same as in uninvolved intima, while the activity of cGMP phosphodiesterase is much lower [97].

These changes clearly explain increased cGMP content in atherosclerotic lesions.

accumulation, and extracellular matrix production [95].

On the basis of numerous data, it can be stated that a decrease in the intracellular content of cAMP and an increase in that of cGMP in atherosclerotic lesions should lead to the stimulation of the main atherosclerotic manifestations at the cellular level, i.e., cell proliferation, lipid

their neighbors are often overladen with lipids [67].

220 Muscle Cell and Tissue

to-cell contacts is a consequence of lipid accumulation.

on these processes [94, 95].

**15. Atherogenic manifestations and cyclic nucleotides**

**Table 2.** The effect of modLDL-induced intracellular cholesterol accumulation on the cAMP and cGMP content in human aortic intimal cells

Bearing in mind the data on cyclic nucleotides, a more precise scheme for the development of atherosclerotic manifestations at the level of subendothelial cells can be proposed. In the intima, modified LDL forms associates or LDL-containing complexes which activate phago‐ cytosis. This reduces cell-to-cell contacts. Since modified LDL is internalized not by the regulated receptor pathway, lipids are accumulated in intimal cells, which decreases intracel‐ lular content of cAMP and increases that of cGMP. This stimulates lipid accumulation, cell proliferation, and extracellular matrix secretion. Presumably, these events occur at the early stages of atherogenesis. Assuming that further development of an atherosclerotic lesion proceeds in the same direction, intracellular lipid content, cell proliferation, and extracellular matrix production should constantly increase. This argues with the observations, cited above, that the intensity of atherosclerotic manifestations decreases in pronounced fibrotic athero‐ sclerotic lesions in comparison with more early lipid-rich lesions and prompts further search for causes of the bell-shaped change in cellular lipidosis as well as in proliferative and synthetic activity observed in atherosclerosis.
