Joshua G. Travers

Cardiac Fibrosis: The Fibroblast Awakens

Myocardial fibrosis is a significant global health problem associated with nearly all forms of heart disease. Cardiac fibroblasts comprise an essential cell type in the heart that is responsible for the homeostasis of the extracellular matrix; however, upon injury, these cells transform to a myofibroblast phenotype and contribute to cardiac fibrosis. This remodeling involves pathological changes that include chamber dilation, cardiomyocyte hypertrophy and apoptosis, and ultimately leads to the progression to heart failure. Despite the critical importance of fibrosis in cardiovascular disease, our limited understanding of the cardiac fibroblast impedes the development of potential therapies that effectively target this cell type and its pathological contribution to disease progression. This review summarizes current knowledge regarding the origins and roles of fibroblasts, mediators and signaling pathways known to influence fibroblast function after myocardial injury, as well as novel therapeutic strategies under investigation to attenuate cardiac fibrosis.

G Protein-Coupled Receptor Kinases in Cardiovascular Disease: Why "Where" Matters

Cardiac function is mainly controlled by β-adrenergic receptors (β-ARs), members of the G protein-coupled receptor (GPCR) family. GPCR signaling and expression are tightly controlled by G protein-coupled receptor kinases (GRKs), which induce GPCR internalization and signal termination through phosphorylation. Reduced β-AR density and activity associated with elevated cardiac GRK expression and activity have been described in various cardiovascular diseases. Moreover, alterations in extracardiac GRKs have been observed in blood vessels, adrenal glands, kidneys, and fat cells. The broad tissue distribution of GPCRs and GRKs suggests that a keen appreciation of integrative physiology may drive future therapeutic development. In this review, we provide a brief summary of GRK isoforms, subcellular localization, and interacting partners that impinge directly or indirectly on the cardiovascular system. We also discuss GRK/GPCR interactions and their implications in cardiovascular pathophysiology.

G Protein-Coupled Receptor-G-Protein βγ-Subunit Signaling Mediates Renal Dysfunction and Fibrosis in Heart Failure.

Development of CKD secondary to chronic heart failure (CHF), known as cardiorenal syndrome type 2 (CRS2), clinically associates with organ failure and reduced survival. Heart and kidney damage in CRS2 results predominantly from chronic stimulation of G protein-coupled receptors (GPCRs), including adrenergic and endothelin (ET) receptors, after elevated neurohormonal signaling of the sympathetic nervous system and the downstream ET system, respectively. Although we and others have shown that chronic GPCR stimulation and the consequent upregulated interaction between the G-protein βγ-subunit (Gβγ), GPCR-kinase 2, and β-arrestin are central to various cardiovascular diseases, the role of such alterations in kidney diseases remains largely unknown. We investigated the possible salutary effect of renal GPCR-Gβγ inhibition in CKD developed in a clinically relevant murine model of nonischemic hypertrophic CHF, transverse aortic constriction (TAC). By 12 weeks after TAC, mice developed CKD secondary to CHF associated with elevated renal GPCR-Gβγ signaling and ET system expression. Notably, systemic pharmacologic Gβγ inhibition by gallein, which we previously showed alleviates CHF in this model, attenuated these pathologic renal changes. To investigate a direct effect of gallein on the kidney, we used a bilateral ischemia-reperfusion AKI mouse model, in which gallein attenuated renal dysfunction, tissue damage, fibrosis, inflammation, and ET system activation. Furthermore, in vitro studies showed a key role for ET receptor-Gβγ signaling in pathologic fibroblast activation. Overall, our data support a direct role for GPCR-Gβγ in AKI and suggest GPCR-Gβγ inhibition as a novel therapeutic approach for treating CRS2 and AKI.

GRK2 in Lymphocytes: Expanding the Arsenal of Heart Failure Prognostics

Heart failure (HF) has been described as the inability of the myocardium to deliver oxygen and nutrients to a degree commensurate with the metabolic requirements of the body.1 Myocardial dysfunction induces compensatory neurohumoral mechanisms, including the sympathetic nervous system (SNS), as an attempt to preserve contractile performance. Mediators of the SNS consist predominantly of 2 catecholamines, namely epinephrine and norepinephrine (NE), released by cardiac sympathetic nerve terminals or secreted directly into the circulation by the adrenal medulla. Effects of these neurotransmitters are mediated through cell surface adrenergic receptors (ARs), members of the G protein–coupled receptor superfamily. Stimulation of the β-AR promotes a conformational change to activate the heterotrimeric G protein Gα and Gβγ subunits, promoting positive inotropic and chronotropic effects culminating in improved myocardial function.2 Article, see p 1116 This functionally beneficial pathway refers exclusively, however, to acute receptor activation; sustained β-AR stimulation, as occurs in most cardiovascular disease, is characterized by molecular modifications, leading to reduced receptor sensitivity and membrane expression. Receptor desensitization and downregulation are regulatory processes thought to moderate persistent agonist stimulation to prevent catecholamine-induced toxicity. The desensitization process is initiated in large part by agonist-dependent phosphorylation of the receptor’s cytoplasmic tail by G protein–coupled receptor kinase 2 (GRK2), a serine/threonine kinase. GRK2 is a cytosolic enzyme that localizes to the plasma membrane after recruitment by active Gβγ subunits. This is followed by recruitment of β-arrestin to the phosphorylated receptor, which prevents recoupling of the dissociated cognate G protein and targets the receptor for internalization and eventual degradation. It is now appreciated that chronic SNS activity and subsequent GRK2-mediated receptor downregulation result in a loss of responsiveness to catecholamines and contribute to further contractile dysfunction and increased patient mortality.2,3 Pivotal studies have indicated that properties of β-AR signaling seem …

Embracing Bias: β1-Adrenergic Receptor–Biased Ligands and Nuclear miRNA Processing

Cardiovascular disease remains the leading cause of mortality and morbidity in the developed world, despite recent advances in therapeutic interventions, with an estimated annual cost in the United States alone of >

Simultaneous adrenal and cardiac g-protein-coupled receptor-gβγ inhibition halts heart failure progression.

312 billion.1 This emphasizes the demand for a greater understanding of the molecular mechanisms involved in cardiovascular pathophysiology and demonstrates the desperate need for innovative strategies for both treatment and prevention.2 Article, see p 833 Recent reports suggest an emerging role for microRNAs (miRs), small noncoding nucleic acid regulators of mRNA, in the development and progression of cardiovascular disease. miRs, a large family of highly conserved RNAs 18-25 nucleotides in length, are essential in the post-transcriptional regulation of gene expression. Typically, miRs are encoded within the introns of protein-coding genes; they also exist intergenically under the control of their own promoters.2,3 Transcription of these regions by RNA polymerase II generates miR precursors known as primary-miRs (pri-miRs), which are converted to mature miRs through the activities of 2 members of the RNase III family of enzymes. Cleavage of pri-miR by the enzyme Drosha forms a ≈70 nucleotide sequence, termed pre-miR, that is subsequently exported to the cytoplasm. Final processing by Dicer creates the ≈20 nucleotide mature miR that incorporates into the miR-induced silencing complex, forming the active enzyme capable of inducing mRNA translational repression or degradation.2,4 Hundreds of distinct mRNAs can be influenced by an individual miR, allowing a single miR or family of miRs to coordinate substantial alterations in physiology and function collectively. It is increasingly clear that appropriate miR expression is crucial in cardiac development, function, and disease. Numerous cardiac complications, including myocardial infarction, hypertrophy, and remodeling, can be exacerbated by improper miR regulation.2,3 Intriguingly, pharmacological modulation of several miRs has been shown to reduce cardiac pathophysiology …