This author interview is by Dr Elizabeth A. Woodcock, of Baker IDI Heart and Diabetes Institute. Dr Woodcock's full paper, Novel Therapeutic Targets in heart failure, is available for download in Clinical Medicine Insights: Therapeutics.

First please summarise for readers the content of your article.

The article discusses approaches to developing inotropic therapies.  We examine ways to increase the Ca²⁺ content of the sarcoplasmic reticulum (SR), because SR Ca²⁺ depletion is central to contractile dysfunction in heart failure.  A number of targets are considered but the focus is on approaches that increase the phosphorylation status of phospholamban (PLN) as this increase SR Ca²⁺ entry.  Approaches that directly phosphorylate PLN are examined, as well as approaches that inhibit dephosphorylation.  We suggest that the newly described interface between phospholipase C beta1b (PLCβ1b) and Shank3 provides a cardiac-specific target for the development of inotropic agents that oppose the dephosphorylation of PLN.  Such therapies would be expected to have fewer undesirable consequences than current inotropic approaches.

How did you come to be involved in your area of study?

We discovered that PLCβ1b showed substantially heightened activity in the myocardium of humans, mice and sheep with heart failure of various aetiologies.  Further, we found that the extent of activation increased with disease progression suggesting a contribution to the disease phenotype. 

What was previously known about the topic of your article?

Phospholipase C subtypes and their relationship to heart disease have previously received little attention.  However, factors both upstream (Gq) and downstream (protein kinase Cα, PKCα) of PLC have previously been shown to cause contractile dysfunction when overexpressed in heart. 

How has your work in this area advanced understanding of the topic?

We have identified PLCβ1b as the cardiac-specific PLC subtype responsible for pathological responses downstream of Gq and we have defined the mechanisms responsible for the exclusive activity of this particular PLC subtype within the myocardium.  Importantly, we have shown that PLCβ1b contributes to cardiac pathology by causing a specific loss of contractile function, associated with PLN dephosphorylation and SR Ca²⁺ depletion.  Importantly, PLCβ1a, the closely related splice variant had no effect on cardiac function thus empowering our work by providing a stringent control for all studies. 

What do you regard as being the most important aspect of the results reported in the article?

In recent studies we have shown that we can limit contractile dysfunction by inhibiting the association of PLCβ1b with Shank3 and this interface provides a platform for the identification of small molecule inhibitors that function as inotropic therapies

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