Leveraging Signaling Pathways to Treat Heart Failure With Reduced Ejection Fraction

Abstract

Advances in the treatment of heart failure with reduced ejection fraction due to systolic dysfunction are engaging an ever-expanding compendium of molecular signaling targets. Well established approaches modifying hemodynamics and cell biology by neurohumoral receptor blockade are evolving, exploring the role and impact of modulating intracellular signaling pathways with more direct myocardial effects. Even well-tread avenues are being reconsidered with new insights into the signaling engaged and thus opportunity to treat underlying myocardial disease. This review explores therapies that have proven successful, those that have not, those that are moving into the clinic but whose utility remains to be confirmed, and those that remain in the experimental realm. The emphasis is on signaling pathways that are tractable for therapeutic manipulation. Of the approaches yet to be tested in humans, we chose those with a well-established experimental history, where clinical translation may be around the corner. The breadth of opportunities bodes well for the next generation of heart failure therapeutics.

NAD+ Metabolism as an Emerging Therapeutic Target for Cardiovascular Diseases Associated With Sudden Cardiac Death

“…RISK pathways are rapidly activated during the first few minutes of reperfusion and have been proposed as a potential therapeutic target for cardioprotective intervention (Hausenloy and Yellon, 2004;Rossello and Yellon, 2018). Noma et al demonstrated that activation of RISK pathways through activation of EGFR signaling confers cardioprotective effect in vivo (Noma et al, 2007;Pinilla-Vera et al, 2019). Mechanistically, RISK pathways reduce the opening probability of mitochondrial permeability transition pore (mPTP) and mPTP-induced cell death in vitro (Davidson et al, 2006).…”

Targeting Ca2 + Handling Proteins for the Treatment of Heart Failure and Arrhythmias

“…Furthermore, aldosterone secretion is enhanced in response to ANG-II signaling and its receptor is upregulated in cardiomyocytes from HFrEF patients (Yoshida et al, 2005). Aldosterone alone is pro-hypertrophic, pro-fibrotic and pro-inflammatory (Pinilla-Vera et al, 2019). Increased neurohormonal signaling can activate the MAPK which, in turn, upregulates pro-hypertrophic gene transcription (Zhang et al, 2003;Nakamura and Sadoshima, 2018).…”

Targeting Protein Kinase G to Treat Cardiac Proteotoxicity

“…However, interest has increased as more and more studies implicate exacerbated disease pathogenesis with proteotoxicity, and the evidence in pre-clinical models that PQC enhancement strategies elicit cardioprotection. PKG is an attractive therapeutic target for multiple reasons: (1) PKG modulators have been used in clinic for decades, (2) PKG activators/stimulators boast an excellent safety profile and are well tolerated, and (3) there are many proteins available to interrogate the PKG pathway (Kokkonen-Simon et al, 2018;Dunkerly-Eyring and Kass, 2019;Pinilla-Vera et al, 2019). The first PKG activators were used in the 1800 s in the form of inhaled organic nitrates to treat angina pectoris (Kots et al, 2009;Daiber and Munzel, 2015).…”

“…Protein kinase G (PKG) elicits cardioprotection during various forms of cardiac stress by transducing a vast array of beneficial processes (Dunkerly-Eyring and Kass, 2019;Pinilla-Vera et al, 2019). PKG stimulates left ventricular relaxation and counters pathological hypertrophy and remodeling (Dunkerly-Eyring and Kass, 2019).…”

“…Insufficient PKG signaling has been implicated in the pathogenesis of cardiac disease toward heart failure, giving considerable interest to strategies to enhance PKG signaling (Kokkonen and Kass, 2017;Dunkerly-Eyring and Kass, 2019). New pharmacological approaches to stimulate PKG are being evaluated as therapy for heart failure and other forms of cardiac disease in clinical trials (Pinilla-Vera et al, 2019). However, a better understanding of the substrates targeted by PKG for cardioprotection is needed.…”