Bim and heart failure
Apoptosis of cardiomyocytes (heart muscle cells) the underlying cause Heart Failure (HF). Excessive stimulation of beta-adrenergic receptors (βAR), either by excessive catecholamine during chronic stress or by autoantibodies, leads to the apoptosis of cardiomyocytes. Work conducted in our lab using transgenic mouse models revealed the molecular mechnism regulating the expression of the apoptotic protein Bim and hence targeting Bim expression offers an avenue for developing new drugs for treating HF.
Despite the common use of βAR antagonists (or β-blockers), heart failure remains poorly controlled with a 5-year survival rate of 50%. Moreover, achieving right dosage without compromising the heart function can be difficult. Patients with unstable hemodynamics usually cannot tolerate β-blockers apparently due to blockade of sympatho-βAR-PKA mediated functional compensation. Therefore there is a need to develop a novel drug that improves the biological properties of the failing heart i.e. one that maintains the β-AR-mediated functional compensation and at the same time is capable of blocking the apoptotic arm of the β-AR pathway.
Our understanding of the molecular regulation of Bim expression during βAR stimulation has helped us to screen for drugs that target only the apoptotic arm of this pathway maintaining the functional compensation arm. These drug hits have the ability to block Bim induction during βAR signalling without having any effect on PKA activity (PKA activity is necessary for the contractile function of the heart). We are currently attempting to improve their in vivo efficacy and conducting pharmacokinetics to understand the drug metabolism.