14 Atherosclerosis Therapies

The new understanding of the crucial role of inflammation in the pathogenesis of atherosclerosis raises questions and opens opportunities for prevention and therapy. Several clinical trials have shown reduction in morbidity and mortality associated with atherosclerosis following treatment with therapeutic agents, some of which originally known for other pharmacological effects. Among drug classes with this quality are statins, ACE-inhibitors and ATII-antagonists, peroxisome proliferator-activator receptor (PPAR)-agonists and antibiotics.

Statins
HMG-CoA-reductase inhibitors (statins) have for some years now been used therapeutically to lower levels of LDL cholesterol. This effect is attributed to their ability to inhibit cholesterol synthesis, leading to an upregulation of hepatic LDL receptors with a corresponding reduction in circulating levels of LDL particles and with this, decreased fuel for atherogenic initiation processes. However, statins have recently been found to possess anti-inflammatory properties independent of LDL reduction, as demonstrated by the beneficial effect in patients with coronary events and an apparently ’normal’ blood cholesterol levels. Mechanisms responsible for this include reduction of plasma hsCRP levels, prevention of LDL oxidation, upregulation of endothelial NO synthetase with improved vasomotion, downregulation of ICAM-1 and thus decreased leukocyte adhesion, inhibition of MØ activation and MMP expression, inhibition of SMC migration, and suppression of production of pro-inflammatory cytokines (6).

Angiotensin converting enzyme-inhibitors and angiotensin II-antagonists
ATII has a wide variety of proatherogenic actions. It is therefore not surprising that ACE-inhibitors and ATII-antagonists are anti-inflammatory (6). This effect has been shown in both animal and human studies where treatment with ACE-inhibitors reduces production/activation of NF-kappaB and several proinflammatory mediators.

Peroxisome proliferator-activator receptor (PPAR)-agonists
PPAR, a nuclear receptor and transcription factor with an important role in regulation of lipid an glucose metabolism, has become the target for different therapeutic agents (6). Originally, the PPAR-agonists were used as insulin sensitizers to treat diabetes, but they have also been shown to protect against atherosclerosis. For example, PPAR-agonists stimulate synthesis of apoA on HDL, with a significant reduction of cholesterol contents in atherosclerotic lesions, and PPAR-agonists also have antiinflammatory properties of potential relevance to atherosclerosis. These include downregulation of expression of vascular adhesion molecules, MMPs, TNF-alpha and other cytokines, probably through interference with NF-kappaB functions.

Antibiotics
Since chronic infections may trigger atherosclerosis, it is reasonable to assume that antibiotics may have a positive effect on the disease process. For example, studies have shown a reduction in human carotid atherosclerotic lesions after treatment of C. pneumoniae infection with roxithromycin. However, because of the long treatment periods that seem necessary in atherosclerosis, prophylactic treatment with antibiotics remains controversial.

Antioxidants
The fact that oxidative mechanisms are involved in atherosclerosis, treatment with antioxidants might have an atheroprotective effect. However, a major antioxidant, a tocopherol (vitamin E), has not yet been shown to effectively inhibit the many oxidation pathways known to occur in human atheroma development. In addition, it has been observed that a tocopherol and ascorbate (vitamin C) under certain conditions show pro-oxidant rather than antioxidant actions. Indeed, the failure of multiple interventional trials with antioxidants has served to question the role of oxidants in the pathogenesis of atherosclerosis (6).

Future therapies
The above-mentioned pharmacological strategies provide an example of unexpected anti-inflammatory effects of existing therapies for atherosclerosis. The emerging data on inflammatory pathways responsible for atherosclerosis, has raised the possibility that future treatments may directly target effectors of inflammation in order to add to the benefit of current treatments. Among potential targets are proximal triggers, such as infectious organisms, transcription factors, proinflammatory cytokines, as well as distal effectors, such as adhesion molecules. The targeting of, for example, NF-kappaB pathways and thus production of proinflammatory cytokines such as TNF-alpha, is an interesting aspect of certain anti-aldosterone drugs (7).


	Inflammation as therapeutic target in atherosclerosis
The new understanding of the crucial role of inflammation in the pathogenesis of atherosclerosis raises questions and opens opportunities for prevention and therapy. Several clinical trials have shown reduction in morbidity and mortality associated with atherosclerosis following treatment with therapeutic agents, some of which originally known for other pharmacological effects. Among drug classes with this quality are statins, ACE-inhibitors and ATII-antagonists, peroxisome proliferator-activator receptor (PPAR)-agonists and antibiotics. Statins HMG-CoA-reductase inhibitors (statins) have for some years now been used therapeutically to lower levels of LDL cholesterol. This effect is attributed to their ability to inhibit cholesterol synthesis, leading to an upregulation of hepatic LDL receptors with a corresponding reduction in circulating levels of LDL particles and with this, decreased fuel for atherogenic initiation processes. However, statins have recently been found to possess anti-inflammatory properties independent of LDL reduction, as demonstrated by the beneficial effect in patients with coronary events and an apparently ’normal’ blood cholesterol levels. Mechanisms responsible for this include reduction of plasma hsCRP levels, prevention of LDL oxidation, upregulation of endothelial NO synthetase with improved vasomotion, downregulation of ICAM-1 and thus decreased leukocyte adhesion, inhibition of MØ activation and MMP expression, inhibition of SMC migration, and suppression of production of pro-inflammatory cytokines (6). Angiotensin converting enzyme-inhibitors and angiotensin II-antagonists ATII has a wide variety of proatherogenic actions. It is therefore not surprising that ACE-inhibitors and ATII-antagonists are anti-inflammatory (6). This effect has been shown in both animal and human studies where treatment with ACE-inhibitors reduces production/activation of NF-kappaB and several proinflammatory mediators. Peroxisome proliferator-activator receptor (PPAR)-agonists PPAR, a nuclear receptor and transcription factor with an important role in regulation of lipid an glucose metabolism, has become the target for different therapeutic agents (6). Originally, the PPAR-agonists were used as insulin sensitizers to treat diabetes, but they have also been shown to protect against atherosclerosis. For example, PPAR-agonists stimulate synthesis of apoA on HDL, with a significant reduction of cholesterol contents in atherosclerotic lesions, and PPAR-agonists also have antiinflammatory properties of potential relevance to atherosclerosis. These include downregulation of expression of vascular adhesion molecules, MMPs, TNF-alpha and other cytokines, probably through interference with NF-kappaB functions. Antibiotics Since chronic infections may trigger atherosclerosis, it is reasonable to assume that antibiotics may have a positive effect on the disease process. For example, studies have shown a reduction in human carotid atherosclerotic lesions after treatment of C. pneumoniae infection with roxithromycin. However, because of the long treatment periods that seem necessary in atherosclerosis, prophylactic treatment with antibiotics remains controversial. Antioxidants The fact that oxidative mechanisms are involved in atherosclerosis, treatment with antioxidants might have an atheroprotective effect. However, a major antioxidant, a tocopherol (vitamin E), has not yet been shown to effectively inhibit the many oxidation pathways known to occur in human atheroma development. In addition, it has been observed that a tocopherol and ascorbate (vitamin C) under certain conditions show pro-oxidant rather than antioxidant actions. Indeed, the failure of multiple interventional trials with antioxidants has served to question the role of oxidants in the pathogenesis of atherosclerosis (6). Future therapies The above-mentioned pharmacological strategies provide an example of unexpected anti-inflammatory effects of existing therapies for atherosclerosis. The emerging data on inflammatory pathways responsible for atherosclerosis, has raised the possibility that future treatments may directly target effectors of inflammation in order to add to the benefit of current treatments. Among potential targets are proximal triggers, such as infectious organisms, transcription factors, proinflammatory cytokines, as well as distal effectors, such as adhesion molecules. The targeting of, for example, NF-kappaB pathways and thus production of proinflammatory cytokines such as TNF-alpha, is an interesting aspect of certain anti-aldosterone drugs (7).