Cardiovascular pathologies

Overview

This main focus of this research group is on the understanding of the underlying mechanisms associated with the pathogenesis of cardiovascular diseases.

The main project areas are on:       

• The inducible L-arginine-nitric oxide pathway      
• Vascular calcification 
• Stem cell differentiation into cardiomyocytes

The inducible L-arginine-nitric oxide pathway

One of the fundamental actions of pro-inflammatory mediators is the induction of the enzyme nitric oxide synthase (iNOS) both in vivo and in a variety of cell types in vitro.

The overproduction of nitric oxide (NO) by iNOS has been implicated as the major cause of some of the deleterious effects in vascular inflammatory diseases such as septic and cytokine-induced circulatory shock.

Studies carried out in our laboratory have shown that uptake of L-arginine via the cationic amino acid transporters (CATs) is increased in cultured cells generating NO, and further established that sustained production of NO under these conditions is critically dependent on the transport of extracellular L-arginine.

These findings suggest that increase in CAT activity may play a critical role in NO formation and regulation of these proteins, in parallel with iNOS, provides a potential therapeutic opportunity for limiting NO production in diseases arising from NO excess.

Our research is therefore focused on obtaining a clear understanding of the regulation of expression and function of the inducible L-arginine-NO pathway in cultured vascular cells using both Pharmacological and molecular approaches. Ongoing studies are aimed at determining the:     

• relationship between CAT expression and function and NO synthesis       
• molecular nature and regulation of expression and function of CATs     
• transport mechanisms for nitric oxide synthase inhibitors      
• signalling for iNOS and/or CATs induction     
• regulation of the inducible L-arginine-NO pathway by statins

Vascular calcification

Calcification is a common occurrence in end-stage renal failure and shows a strong correlation with declining renal function.

It often results in a diverse range of pathologies including calcific uraemic arteriolopathy, solid as well as extra-osseous soft tissue calcification of which vascular calcification (VC) is the most common and often the most clinically relevant corollary.

The existence of VC in chronic kidney disease (CKD) results in increased arterial stiffness, becoming predictive of secondary cardio-vascular complications with high morbidity and mortality.  

The precise mechanisms that lead to VC in CKD subjects are poorly understood but it is accepted to be a delicate and well-controlled biological process that results in smooth muscle cells (SMCs) gaining an osteoblastic phenotype.

These complex changes may be regulated in vivo by circulating factors in plasma but it is not entirely clear how the various molecules act, nor is the complex interplay amongst the key factors established. Moreover, it is not clear whether the presence of the various factors in serum may be sufficient to regulate calcification outside of disease settings.  

Our research in this area is aimed at establishing the in vitro calcific potential (ie ability to induce calcification) of serum and determining whether in vitro calcific potential correlates with the degree of renal impairment in vivo.

In parallel, we are also interested in identifying critical biomarker surrogates and mechanisms responsible for the calcific potential of the serum. This may lead to the development of diagnostic tools and inform therapeutic strategies.

Stem cell differentiation into cardiomyocytes

Myocardial infarction has remained one of the most frequent causes of death in the western world. Although progress is being made in reducing mortality with conventional therapies, there is still no cure for the damaged myocardium other than heart transplant.

This approach is however limited by the availability of donors and the potential need for life long immunosuppressive therapy.

The advent of stem cell (SC) research has raised the possibility of restoring normal cardiac function through tissue regeneration using transplanted SCs.

This novel approach is however restricted by the poor survival of SCs within the ischaemic myocardium and by the fact that SCs differentiate into multiple lineages.

The mechanisms that regulate SC apoptosis and the precise signalling that controls their differentiation into cardiomyocytes are still poorly understood.

Our research is therefore aimed at understanding the cellular mechanisms that promote stem cell survival and direct their differentiation into cardiomyocytes.

In parallel we are also interested in identifying endogenous bioactive molecules that may mediate the differentiation process in vivo.