Cerebral cavernous malformations (CCM) are irregular clusters of dilated, leaky capillaries found in the central nervous system in around 0.5% of the general population. Although many of those with the condition will never be aware of the fact, for others the symptoms can be severe. Depending on the specific location of the CCM in the brain or spinal cord, patients may experience seizures, headaches, paralysis, hearing or vision changes, and cerebral haemorrhage. Current treatment options rely on management of the symptoms (e.g. control of seizures with anti-epileptic drugs) or surgical resection.

Researchers at University of North Carolina School of Medicine, Chapel Hill have now identified a potential target for therapeutic intervention in CCM. The disease is associated with mutations in any of three genes, ccm1, ccm2 or ccm3, which encode the corresponding CCM-1, -2 and -3 proteins. These proteins form a common complex and act co-ordinately in regulation of the cytoskeleton. It had previously been shown that loss of CCM-2 resulted in overexpression of the GTPase, RhoA, but this latest study demonstrates that CCM-1 and CCM-3 are also required for regulation of RhoA.

The team were able to restore normal function to endothelial cells lacking CCM-1, -2 or -3 by inhibition of the RhoA-activated Rho Kinase (ROCK), either using an inhibitor, Y-27632, or shRNA knockdown of ROCK2. The results suggest that inhibition of ROCK may represent a target for pharmacological intervention in this disease.

The study is published in the Journal of Biological Chemistry.

An aortic aneurysm is a bulge in the aorta, the largest blood vessel in the body, which results from weakening of the artery wall. The majority of these occur in the portion of the aorta that passes through the abdomen and are referred to as abdominal aortic aneurysms (AAA). AAA is something of a stealth disease, since it is generally asymptomatic and may only be diagnosed at a routine physical examination or following X-ray. Over time the aneurysm may expand, with an increased risk of rupturing. Unfortunately, the rapid blood loss following aneurysm rupture is frequently fatal and accounts for at least 15,000 deaths in the US annually.

The only treatment for AAA currently available is surgical intervention. Early diagnosis is followed by monitoring the size of the aneurysm until the risk of rupture exceeds the risk of surgery. However, scientists at Providence Heart + Lung Institute at St. Paul’s Hospital and the University of British Columbia (UBC) have now raised the possibility of pharmacological intervention. Using experimental models of AAA, the team have found a role for the protein-degrading enzyme Granzyme B (GMZB).

GMZB is a serine protease expressed by a variety of immune cells and is responsible for destroying unwanted tissue, such as virally-infected cells. This role is supported by the pore-forming protein, perforin, which delivers GMZB to the intracellular compartment. The UBC research has shown that GMZB, which is abundantly expressed in aneurysms from human and animal model AAA, also plays a role in the pathogenesis of AAA. Further, the experimental data suggest that this is a perforin-independent mechanism involving extracellular matrix degradation and subsequent loss of vessel wall integrity. The results suggest that an inhibitor of GMZB may provide a therapeutic option in the treatment of AAA.

The study is published in the American Journal of Pathology.

Atherosclerosis is caused by a build up of lipids, cholesterol, calcium, and cellular debris within the artery, resulting in plaque formation. This restricts the flow of blood and decreases oxygen supply to target organs, increasing the risk of cardiovascular diseases including heart attacks and stroke. The true incidence of atherosclerosis is difficult, if not impossible, to determine since it is predominantly asymptomatic, but the ensuing cardiovascular diseases are the leading cause of death in many Western societies. Risk factors for atherosclerosis include high blood pressure and a high fat diet and current non-surgical treatments, such as antihypertensive medicines and statins, focus on reducing these risks.

The precise mechanisms underlying atherogenesis are unclear but scientists at Imperial College London have now identified a pathway that plays a key role in the inflammation and matrix degradation characteristic of human atherosclerosis.

The researchers studied sections of carotid artery taken from 58 stroke patients and found that toll-like receptor 2 (TLR-2) was unusually active in the plaques. TLRs are expressed on immune cells and play a fundamental role in pathogen recognition and innate immunity, mediating release of cytokines and other inflammatory mediators. One arm of the TLR-induced inflammatory response is dependent on a signalling pathway that is mediated by the adaptor molecule, myeloid differentiation primary response gene 88 (MyD88), and the study showed that a dominant-negative form of MyD88 decreased the production of MCP-1, IL-8, IL-6, MMP-1 and MMP-3 as well as NF-κB activation in cell cultures prepared from the carotid arteries. TLR-2 neutralizing antibodies were also shown to inhibit NF-κB activation and significantly reduce MCP-1, IL-8, IL-6, MMP-1, MMP-2, MMP-3, and MMP-9 production. In contrast, an IL-1R antagonist, TLR-4 blocking antibodies, or overexpression of a dominant-negative form of the TLR-4 signalling adaptor, TRIF-related adaptor molecule, reduced NF-κB activity but did not have a broad impact on the production of the inflammatory mediators studied.

The authors hope that TLR-2 blockers might be developed to prevent or treat atherosclerosis and the resulting cardiovascular disease without compromising the ability to fight infection.

The study is published in the journal Circulation.

Pulmonary arterial hypertension (PAH) is a progressive, debilitating disease characterised by increased resistance in pulmonary arteries, placing additional workload on the right ventricle of the heart. Untreated, the disease frequently results in right ventricular failure and death. Until the 1990s the only effective treatment was heart-lung transplantation. Subsequently, drug treatments that have been used include anticoagulants, calcium channel blockers, prostacylin and endothelin receptor antagonists. Whilst these drugs have demonstrated efficacy in PAH patients, delaying the need for lung transplantation, long term survival rates have not been significantly impacted.

The annual incidence of PAH is around 1-2 per million individuals, with a further 8 per million contributed by PAH associated with scleroderma. Despite the low incidence, there are approximately 100,000 PAH patients in Europe and the US.

Scientists at University of California–San Diego (UCSD) have now established that human pulmonary hypertension is characterised by overexpression of Notch3 in small pulmonary artery smooth muscle cells and that the severity of disease in humans and rodents correlates with the amount of Notch3 protein in the lung. In the study, published online in Nature Medicine on 25^th October, the team showed that mice with homozygous deletion of Notch3 do not develop pulmonary hypertension in response to hypoxic stimulation. Additionally, mice with pulmonary hypertension were successfully treated with a DAPT, a γ-secretase inhibitor that blocks activation of Notch3.

Notch receptor signalling is implicated in control of smooth muscle cell proliferation and maintaining smooth muscle cells in an undifferentiated state. The discovery that the Notch3 signalling pathway is crucial for the development of PAH provides a novel target for therapeutic intervention.

Selective cyclooxygenase-2 (COX-2) inhibitors were developed to reduce the risk of gastrointestinal side effects associated with the older non-steroidal anti-inflammatory drugs (NSAIDs) which inhibit both COX-1 and COX-2. The withdrawal of rofecoxib (Vioxx™) in 2004 and valdecoxib (Bextra™) in 2005 because of a slightly increased risk of thrombotic events such as heart attacks and strokes after long-term treatment came as a blow to the pharmaceutical industry, doctors and patients. Since the withdrawal of rofecoxib and valdecoxib, no new anti-inflammatory drugs have been submitted to the FDA for the treatment of osteoarthritis.

Last month, however, French pharmaceutical company, NicOX, submitted an NDA for its first-in-class cyclooxygenase-inhibiting nitric oxide donator (CINOD), naproxcinod, for the treatment of osteoarthritis.

Naproxcinod is a nitroxybutyl ester of the well established and well tolerated NSAID, naproxen, and is intended to overcome another drawback of NSAIDs and COX-2 inhibitors – increased blood pressure. Cleavage of naproxcinod by esterases gives naproxen, together with a nitric oxide donating moiety. Nitric oxide relaxes vascular smooth muscle cells, causing dilation of the arteries and reducing blood pressure, and has also been reported to reduce formation of thrombi. In clinical trials in patients with osteoarthritis of the knee and hip, naproxcinod met efficacy endpoints and did not cause an increase in blood pressure. Naproxcinod also showed an advantage compared with naproxen in terms of gastrointestinal side effects.

Although sildenafil (Viagra®) is best known for the treatment of erectile dysfunction, it also reduces pulmonary hypertension and its use in the treatment of heart failure and cardiac hypertrophy is being investigated.

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5) which enhances nitric oxide-mediated vasodilation by preventing breakdown of the intracellular second messenger, cyclic guanosine monophosphate (cGMP). Phosphodiesterases regulate cGMP-dependent signalling pathways including control of Ca²⁺ concentrations which, as well as modulating the strength of contractions, are believed to regulate myocyte growth and hypertrophy. At least five PDE families (PDE1-5) are expressed in the human heart and a study led by researchers at the University of Rochester Medical Center has now shown that the Ca²⁺/calmodulin-activated phosphodiesterase type 1 (PDE1) enzymes play a major role in cardiac disease.

Either down-regulation of PDE1 using siRNA or treatment with the selective inhibitor, IC86340, prevented phenylephrine-induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal rat ventricular myocytes and adult rat ventricular myocytes. Studies in mice showed that IC86340 also reduced the cardiac hypertrophy caused by chronic infusion of isoproterenol. Although both PDE1a and PDE1c mRNA and protein were detected in human hearts, only PDE1a was found in rodent hearts. PDE1a is also up-regulated in heart tissue from various animals that model pathological hypertrophy, suggesting that PDE1a plays a key role in mediating pathological cardiomyocyte hypertrophy. Studies in isolated myocytes showed that a combination of sildenafil and IC86340 reduced hypertrophy more than either compound alone and the team now plan to explore the effects of combination treatment in animal studies.

The study is published in the journal Circulation Research.

Both high blood pressure and atherosclerosis, a condition in which the arteries become narrowed by atheroma, are major risk factors for cardiovascular diseases, including heart attack and stroke. The atheromatous plaques are made up of cells (mostly macrophages) or cell debris containing oxidised lipids, calcium and connective tissue.

A team led by scientists in the UK has now shown that matrix metalloproteinase-8 (MMP8) plays a crucial role both in raising blood pressure, and in causing the abnormal build-up of cells and fatty deposits in the arteries. MMPs are best known for their ability to degrade extracellular matrix proteins such as collagen, but have also been shown to cleave a variety of other proteins. As well as degrading collagen type 1, MMP8 has been shown to cleave angiotensin I to produce the vasopressor, angiotensin II. This conversion is also carried out by angiotensin converting enzyme (ACE) and ACE inhibitors are commonly prescribed to treat patients with high blood pressure and congestive heart failure as well as those who have suffered a heart attack. In the present study, the team found that inactivating MMP8 in apolipoprotein E-deficient mice – which are prone to atherosclerosis – resulted in a substantial reduction in atherosclerotic lesions and that the lesions had fewer macrophages but increased collagen content. The knockout mice were also found to have reduced levels of angiotensin II and lower blood pressure, as well as reduced expression of vascular cell adhesion molecule (VCAM)-1 in atherosclerotic lesions.

The team also evaluated data from a group of 2000 patients with coronary artery disease who were undergoing a coronary angiogram procedure and found an association between an MMP8 gene variant and degree of atherosclerosis. The researchers hope that their findings will lead to new drugs to treat hypertension and prevent heart disease, particularly for patients who fail to respond well to ACE inhibitors.

The study is published in the journal Circulation Research.

The renin-angiotensin system (RAS) was first studied for its role in regulation of the cardiovascular system and drugs that modulate the RAS are now widely used to treat high blood pressure, myocardial infarction and stroke. More recently, it has become apparent that components of the RAS also mediate inflammatory processes and two recently published studies have now expanded on the link between the RAS and multiple sclerosis (MS). A team led by researchers at Stanford University School of Medicine found that multiple sclerosis lesions from brains of MS patients had elevated levels of both the angiotensin I receptor (AT₁R) and angiotensin converting enzyme (ACE). The team then showed that treatment with the ACE inhibitor, lisinopril, or the AT₁R antagonist, candesartan, could prevent the development of experimental autoimmune encephalomyelitis (EAE) in mice and, perhaps more importantly, reverse the symptoms of established disease. Reduced activation of AT₁R was shown to increase the number of T_reg cells in the CNS and suppress TH1/TH17-mediated immune responses to autoantigens.

The study is published in the online early edition of PNAS.

The second study, by researchers in Germany and also published in the online early edition of PNAS, showed that renin, ACE and AT₁R were all up-regulated in the inflamed spinal cord and immune system, including antigen presenting cells (APC), of mice with EAE. Pretreatment with the renin inhibitor, aliskiren; the ACE inhibitor, enalapril; or the AT₁R antagonist, losartan, reduced the severity of EAE symptoms and losartan was also found to ameliorate the course of established disease. Blockade of AT₁R was found not to have a direct effect on T-cell responses but to significantly reduce APC in the spinal cord and immune organs, and to reduce cytokine-induced APC migration.

Since drugs that modulate the RAS have been used in millions of people around the world and have few side effects, the researchers hope that clinical trials to test their effectiveness in MS patients should be straightforward to carry out.

A number of organs, including the heart, have limited regenerative powers, but US scientists have now shown that fully differentiated cardiac muscle cells can be induced to proliferate and regenerate. Writing in the journal Cell, they show that the growth factor neuregulin 1, which plays a role in early development of the heart and nervous system, induces mononucleated, but not binucleated, cardiomyocytes to divide in vitro by acting on the receptor tyrosine kinase, ErbB4. In mice, genetic inactivation of ErbB4 was shown to reduce cardiomyocyte proliferation, whereas increasing ErbB4 expression enhanced proliferation. Following heart attack in adult mice, daily intraperitoneal injection of neuregulin 1 for 12 weeks led to regeneration of the heart muscle and improved function. Unlike the control mice, the treated animals showed reduced signs of heart failure such as left-ventricular dilation and cardiac hypertrophy. If the neuregulin/ErbB4 signalling pathway plays the same role in human heart muscle, stimulating proliferation of differentiated cardiomyocytes by activation of this pathway may provide an alternative to stem cell therapy to regenerate damaged heart muscle in patients with heart failure or children with congenital heart defects. Since ErbB receptor tyrosine kinases and neuregulins have oncogenic potential and may cause proliferation of other tissues, a full safety assessment would be needed before any clinical studies.

Neuregulin 1 has previously been associated with susceptibility to schizophrenia and has also been shown to protect neurones following stroke.

Human cytomegalovirus (hCMV) is a widespread member of the herpes family of viruses, with well over half of the world’s adult population thought to be infected. Most individuals are infected in early childhood and remain infected with latent virus for the rest of their lives. For the majority of people, infection is asymptomatic and usually undiagnosed but immunosuppression, caused by HIV-1 infection or drug therapy after transplant surgery, can lead to reactivation of the virus and overt infection. A number of studies have linked hCMV infection to cardiovascular disease, but the mechanisms underlying the pathology are not well understood. Writing in the May 15^th edition of PLoS Pathogens, a team led by researchers at Beth Israel Deaconess Medical Center have now shown that infection with murine CMV (mCMV) leads to a significant increase in arterial pressure in mice. mCMV infection alone was sufficient to cause the observed increase in blood pressure. mCMV infection alone did not cause atherosclerosis in the aorta but, when combined with a high cholesterol diet, did cause classic plaque formation. The team went on to show that mCMV stimulated production of pro-inflammatory cytokines, IL6, TNF-α and MCP-1 which have previously been linked to high blood pressure. They also showed that mCMV infection induced renin expression in an infection dose-related manner in mouse renal cells and that hCMV induced a similar increase in human vascular endothelial cells. In mice, mCMV infection was additionally shown to lead to an increase in angiotensin II levels in serum and in tissue from the aorta.

Since the roles of renin and angiotensin II in hypertension are well established, the study provides a mechanism by which persistent CMV infection might increase blood pressure and also suggests that vaccination or antiviral therapy could have the potential to provide new treatments for cardiovascular disease.