Left ventricular hypertrophy represents the hearts response to increased biomechanical stress such as arterial hypertension or valvular heart disease. Cardiac hypertrophy has traditionally been considered a compensatory mechanism required to normalize wall tension and to maintain cardiac output. However, recent clinical studies as well as several animal models have shown that sustained cardiac hypertrophy is rather a maladaptive process, ultimately leading to heart failure and sudden death independent of the underlying cause of hypertrophy. Throughout the past decade, much effort has thus been spent on deciphering the molecular signaling pathways mediating cardiac growth. Identification of novel molecules regulating cardiac hypertrophy could offer the basis for a new generation of cardiovascular drugs. In this review we focus on recent insights into hypertrophic signaling and consider current and emerging approaches to inhibit hypertrophy with the ultimate goal to prevent or delay the onset of heart failure and sudden death in patients.
The Liver X Receptor (LXR) α and β isoforms are members of the type II nuclear receptor family which function as obligate heterodimers with the Retinoid X Receptor (RXR). Upon agonist binding, the DNA Binding Domain (DBD) of LXR interacts with LXR response elements on target genes to initiate transcription. A number of genes have been shown to be modulated by LXR function, including the ATP-binding cassette transporter A1 (ABCA1). ABCA1 is involved in the process of reverse cholesterol transport (RCT) from macrophages in atherosclerotic plaques to highdensity lipoproteins (HDL) in the plasma. Both homozygous and heterozygous mutations in ABCA1 result in conditions characterised by decreased levels of HDL and an earlier onset of atherosclerosis. A number of other genes are upregulated by LXR activation which would be expected to have either pro- or anti-atherogenic effects. One such target gene is sterol regulatory element binding protein-1c (SREBP-1c), which is involved in the process of lipogenesis leading to increased levels of triglycerides which are pro-atherogenic. The complexity of LXR responses, however, makes it difficult to extrapolate the positive or negative effects of each target gene in isolation to a conclusion as to the outcome in humans when all target genes are being modulated in concert. This review will cover the structural features and associated biological data of non-steroidal LXR modulators claimed for the treatment of cardiovascular disease, as well as highlighting preferred compounds where this information can be discerned. In addition to this patent information a précis of literature data relevant to the utility of specific compounds in the treatment of cardiovascular disease will be given where available.
Basic and clinical investigation into many of the diverse aspects of cardiovascular drug discovery employs varied approaches aimed at determining physiologic and pathophysiologic efficacy of candidate agents for therapeutic utility with the ultimate hope of identifying those agents capable of exerting salutary influence upon cardiac and vascular tissues. Promising compounds may then be used for prophylactic cardiovascular protection and for the treatment of various disorders including hypertension, cardiomyopathy, occlusive vascular disease, and heart failure. The invention disclosed in Methods for identifying cardiovascular agents  provides screening methods which can be used to identify certain suspected cardiovascular agents that inhibit vascular smooth muscle cell (VSMC) activation and/or proliferation, functional adaptations inherent in the responses to disease or injury, or those that enhance vascular endothelial cell (VEC) activation and/or proliferation, processes thought to provide protection to jeopardized blood vessels. Additionally, these screening assays include agents that activate estrogen responsive genes in vascular cells, considering that estrogen signaling is generally suggested to serve pivotal functions in preventing many of the pathologic mechanisms contributing to occlusive vascular complications. The findings of this primary patent are directly relevant for discoveries in related inventions that disclose various provisions for cardiovascular drug discovery. This review will provide detailed synopses of these function-based screening methods capable of identifying cardiovascular protective agents for use in basic science research and clinical drug discovery.
Currently available drug-eluting stents have been shown to reduce the prevalence of in-stent restenosis. However, their use is limited by their enormous cost and unwanted side effects associated with both drugs, sirolimus and paclitaxel, presently used to coat most of the stents clinically avilable. Due to their lack of selectivity with respect to targeted cell types these drugs do not only inhibit vascular smooth muscle cell proliferation underlying neointima formation, they also compromise endothelial repair increasing the risk for subacute thrombosis following implantation of drug-eluting stents. Accordingly, there is need for new costeffective agents capable to inhibit restenosis without clinically relevant, unwanted side effects. In the present paper a selection of the most important patent applications published within the last 3 years and claiming the use of homologous cellular and extracellular agents as therapeutics or targets to prevent restenosis are reviewed. Such agents include c-Jun, the focal adhesion kinase (FAK) and its inhibitor FAK-related non-kinase (FRNK), estrogen receptors, variants of vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) as well as some so far poorly characterized factors supposedly involved in the control of cell proliferation, inflammation and apoptosis. Such agents promise to be cost-effective and, in some cases, potentially devoid of unwanted side effects. Clinical long-term studies have yet to support such notions.
Epoxide hydrolases are a group of enzymes that convert the epoxide group of chemical compounds to corresponding diols by the addition of water. Soluble epoxide hydrolase (sEH, formerly referred to as cytosolic epoxide hydrolase), which is widely distributed in mammalian tissues, is the primary enzyme responsible for the conversion of epoxyeicosatrienoic acids (EETs), the bioactive lipid mediators formed from arachidonic acid by cytochrome P450 epoxygenase, to their corresponding diols. EETs, but not their diols, are endogenous anti-hypertensive eicosanoids. Disruption of the sEH gene in male mice decreases blood pressure, and inhibition of sEH decreases blood pressure in several experimental hypertensive models. Potent selective sEH inhibitors have been developed, and these sEH inhibitors have potential to become a novel class of anti-hypertensive drug.
Although statins are effective in reducing cardiovascular risk, combination therapy may be required to meet recommended target LDL-C levels. However, the utility of current combination therapies with niacin or bile acid sequestrants is limited by side effects and compliance. Ezetimibe, as a selective cholesterol absorption inhibitor, represent a new class of pharmaceutical agents. The combination of ezetimibe with statins has shown a 16-21% increase in the percentage of patients achieving their ATP III LDL-C goal. Randomized, double-blind studies have shown that coadministration of ezetimibe with simvastatin is well tolerated, causing dose-dependent reduction in LDL-C and total cholesterol levels, with no apparent effect on high-density lipoprotein cholesterol or triglycerides. Even in diabetes mellitus type 2 patients; the addition of ezetimibe 10 mg to simvastatin 20 mg is more efficacious than doubling the dose of simvastatin in lowering lipid parameters. Similarly the coadministration of ezetimibe and rosuvastatin, has shown a mean incremental reduction in LDL-C of -16%, compared with rosuvastatin alone, while there was no apparent effect on HDL-C or triglycerides. Ezetimibe and fenofibrate co-administration has shown also improvement in the lipid/lipoprotein profile. The combination therapy with ezetimibe and statin or fibrate may be an effective therapeutic option for patients with dyslipidemia.
There is a growing body of evidence that the renin-angiotensin system (RAS) plays a pivotal role in the pathogenesis of cardiovascular diseases. Indeed, large clinical trials have demonstrated substantial benefit of the blockade of this system for cardiovascular-organ protection. Although several types of angiotensin II type 1 (AT1) receptor blockers (ARBs) are commercially available for the treatment of patients with hypertension, we have recently found that telmisartan (Micardis) could have the strongest binding affinity to AT1 receptor. Telmisartan will be a promising cardiometabolic sartan due to its unique peroxisome proliferator-activated receptor-γ (PPAR-γ)-inducing properties as well. In this review, we focused on telmisartan, and discussed its potential therapeutic implications in cardiometabolic disorders.
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a strong novel free radical scavenger, is used for treatment of patients with acute brain infarction. Edaravone has preventive effects on myocardial injury following ischemia and reperfusion in patients with acute myocardial infarction. Antioxidant actions of edaravone include enhancement of prostacyclin production, inhibition of lipoxygenase metabolism of arachidonic acid by trapping hydroxyl radicals, inhibition of alloxan-induced lipid peroxidation, and quenching of active oxygen, leading to protection of various cells, such as endothelial cells, against damage by reactive oxygen species (ROS). Recently, we have shown that edaravone improves endothelial function through a decrease in ROS in smokers. From a clinical perspective, it is important to select an appropriate drug that is effective in improving endothelial function in patients with cardiovascular diseases. The novel free radical scavenger edaravone may represent a new therapeutic intervention for endothelial dysfunction in the setting of atherosclerosis, chronic heart failure, diabetes mellitus, or hypertension. This review focuses on clinical findings and on putative mechanisms underlying the beneficial effects of the antioxidative agent edaravone on the artherosclerotic process in patients with cardiovascular diseases.
The discovery of endothelin two decades ago has now evolved into an intricate vascular endothelin (ET) system. Several ET isoforms, receptors, signaling pathways, agonists, antagonists, and clinical applications have been identified and documented in first-rate patents. The role of ET as one of the most potent endothelium-derived vasoconstricting factors is now complemented by a newly discovered role in vascular relaxation. ET synthesis is initiated by the transcription of ET genes in endothelial cells and the generation of the gene products preproET and big ET, which are further cleaved by specific ET converting enzymes into ET-1, -2, -3 and -4 isoforms. ET isoforms bind with different affinities to ETA and ETB2 receptors in vascular smooth muscle, and stimulate [Ca2+]i, protein kinase C, mitogen-activated protein kinase and other signaling mechanisms of smooth muscle contraction, growth and proliferation. ET also binds to endothelial ETB1 receptors, which mediate the release of vasodilator substances such as nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor. Endothelial ETB1 receptors may also function in ET re-uptake and clearance. Although the effects of ET on vascular function and growth are well-recognized, the role of ET and its receptors in the regulation of blood pressure and in the pathogenesis of hypertension is not clearly established. Salt-dependent hypertension in experimental animals and some forms of moderate to severe hypertension in human may show elevated levels of plasma or vascular ET; however, other forms of hypertension show normal ET levels. The currently available ET receptor antagonists reduce blood pressure in some forms of experimental hypertension. Careful examination of recent patents may identify more effective and specific modulators of the vascular ET system for clinical use in human hypertension.
Atherosclerosis is the leading cause of death and disability in the developed world. Although the low-density lipoprotein (LDL) cholesterol lowering drugs reduce the mortality and morbidity associated with coronary artery disease, considerable mortality and morbidity remains. Reverse cholesterol transport mediated by high-density lipoproteins (HDL) may provide an independent pathway for lipid removal from atheroma. The current NCEP ATPIII include HDLcholesterol ≥1.6 mmol/l as a negative risk factor. Torcetrapib is an inhibitor of cholesteryl ester-transfer protein (CETP) that increases high-density lipoprotein (HDL) cholesterol levels. The drug increases HDL-cholesterol and apolipoprotein A-I levels and decreases LDL-cholesterol and apolipoprotein B levels. The effect is showed in monotherapy and when administered in combination with statins. In addition, torcetrapib did not significantly change the serum levels of cholesterol and triglycerides. The raising HDL-cholesterol with torcetrapib could be a new approach to atherosclerotic cardiovascular disease although new trials based on hard clinical end points are necessary.