Members of the toll-like receptor (TLR) family of transmembrane proteins are the central actors in innate immunity, the fast and immediate immune response to pathogens that invade the body. As of 2010, 11 TLRs had been discovered in humans. Foreign proteins, such as the bacterial membrane protein lipopolysaccharide (LPS), bind the receptors, triggering an intracellular signaling cascade that activates genes important to the immune response, including the pro-inflammatory transcription factor NF-kB. This mediation of the inflammatory response is thought to play a role in cardiovascular disease, particularly atherosclerosis and ischemic cardiac injury (i.e. lack of oxygen to the heart muscle) leading to heart failure.
TLRs in the cardiovascular system
Various members of the toll-like receptor family are expressed in cardiomyocytes and arterial endothelium. Their expression in the heart appears to be up-regulated in heart failure. In addition, researchers have noted that the number of circulating TLR-positive monocytes (a type of white blood cell) is increased in some forms of cardiovascular disease. Studies in neonatal rats have shown that blocking TLR2 reduces cell death and cytotoxicity in the context of oxidative stress. Mice who lack TLR2 altogether (TLR2-/- or TLR2 null mice) have preserved left ventricular function in heart failure, whereas normal mice who express the receptor more often have dilatation of the left ventricle, leading to death.
In contrast, activating TLR4 reduces nitric oxide synthase (NOS) 2-mediated apoptosis of cardiomyocytes. In fact, TLR4 has been found to be up-regulated in heart failure, perhaps part of an activated protective mechanism against damage. However, it is also implicated in atherosclerosis.
TLR-mediated disease
The research on TLRs in cardiovascular disease is only about a decade old. The first TLR was discovered in 1997 (in fruit flies, Drosophila), and the first papers recognizing a potential role in heart disease were first published in 2001. The receptors are now thought to play a role in extracellular matrix remodeling. For example, TLR4 is thought to be involved in neointima formation (restructuring of the interior arterial wall). Activation of the toll-like receptors by host molecules could result in aberrant signaling and self-destructive functions against the host tissues.
TLR4 has been found to be capable of responding to stress and cell damage, including host heat-shock proteins. Neointima formation in an intact artery can contribute to the development of atherosclerotic plaques. When present in the coronary arteries, these plaques can cause a heart attack (i.e. myocardial infarction) by blocking the flow of blood, and thus oxygen, to the heart muscle. The TLRs on immune cells have also been shown to be activated by non-infectious stimuli, and even some therapeutic drugs.
Role of pathogens and genetics
Polymorphisms, or slight variations, in the genes encoding the TLRs could cause more specific binding to host molecules in individuals who express the variants. This could, in turn, increase the risk of certain individuals being more susceptible to cardiovascular disease because the receptors on their cells are overactive, or even binding to molecules they shouldn’t. The polymorphisms that may contribute are not yet known as the studies on two polymorphisms in the TLR4 gene have been inconclusive. Some disease mechanisms are also thought to trigger an overactive TLR response, which may or may not be genetically linked. Chlamydia pneumoniae is one such pathogen, having been found in atherosclerotic plaques, though its role in TLR-mediated cardiovascular disease is unclear.
The toll-like receptors are necessary components of the immune response, but when not working properly or in yet defined contexts they can mediate damage to the heart and cardiovascular system. Contributing factors for the role of TLRs in cardiovascular disease are still unknown.
