Molecular cardiology in translation: gene, cell and chemical-based experimental therapeutics for the failing heart

Abstract

Acquired and inherited diseases of the heart represent a major health care issue in this country and throughout the World. Clinical medicine has made important advancements in the past quarter century to enable several effective treatment regimes for cardiac patients. Nevertheless, it is apparent that even with the best care, current treatment strategies and therapeutics are inadequate for treating heart disease, leaving it arguably the most pressing health issue today. In this context it is important to seek new approaches to redress the functional deficits in failing myocardium. This review focuses on several recent gene, cell and chemical-based experimental therapeutics currently being developed in the laboratory for potential translation to patient care. For example, new advances in bio-sensing inducible gene expression systems offer the potential for designer cardio-protective proteins to be expressed only during hypoxia/ischemia in the heart. Stem cells continue to offer the promise of cardiac repair, and some recent advances are discussed here. In addition, discovery and applications of synthetic polymers are presented as a chemical-based strategy for acute and chronic treatment of diseased and failing cardiac tissue. Collectively, these approaches serve as the front lines in basic biomedical research, with an eye toward translation of these findings to clinically meaningful applications in cardiac disease.

Keywords: Cardiac; Heart; Translational.

Fig. 1

Overview of experimental strategies to reverse pump dysfunction in failing heart. Use of viral mediated gene transfer, chemical-based membrane sealants, and stem cells are experimental strategies for treatment of acute and chronic heart failure. Therapies can be envisioned to be used preemptively to prevent injury induced cardiomyopathy in susceptible population. Alternatively, post-injury treatment could halt or perhaps reverse disease progression

Fig. 2

Design and implementation of genetic biosensors in the heart. Double oxygen-sensing vector system for highly-sensitive gene activation during ischemia/hypoxia. a Schematic diagram of vector construction including the double oxygen sensor vector containing repeated HRE moieties and ODD element driving expression of a GAL4-ODD-P65 fusion protein and the effector vector containing repeated UAS moieties driving expression of a gene of interest. b Under baseline normoxic conditions GAL4 is degraded preventing expression of the effector vector. During myocardial ischemia (low oxygen tension), GAL4 is stabilized and activates effector vector gene transcription allowing for cellular accumulation of therapeutic protein protecting cardiac function. During recovery from injury oxygen tension is restored resulting in suppression of GAL4 and inactivation of effector gene expression. HRE Hypoxia responsive element, ODD oxygen-dependent degradation domain

Fig. 3

Protein biosensors for enhanced heart performance. Histidine-modified cardiac troponin I acts as a molecular rheostat sensing altered intracellular milieu of the injured heart. a The heterotrimeric troponin complex is part of the thin filament in the sarcomere and functions as the molecular switch to regulate contraction. b Differences in the primary amino acid sequence of troponin I led to the discovery of a critical histidine residue in ssTnI which conferred pH-dependent activation of the myofilament. This histidine was substituted for an alanine at codon 164 of cTnI (cTnI A164H) to confer this biochemical advantage to the adult cardiac TnI isoform. c Under baseline conditions cTnI A164H has similar functional characteristics as WT cTnI in vitro and in vivo. However, under conditions of ischemia/hypoxia stress, protonation of the histidine in cTnI A164H protects myofilament calcium responsiveness thus protecting cardiac function compared to WT cTnI

Fig. 4

Membrane sealants for failing myocytes. Membrane fragility is an important pathophysiological mechanism in heart failure. Ultimately, the failure of the membrane barrier places significant stress on an already compromised myocyte. The use of membrane sealant Poloxamer 188 (shown in figure) may have utility in limiting the consequences of membrane damage, by restoring the barrier function to the disrupted lipid bilayer