Excessive extracellular matrix (ECM) deposition is a defining feature of cardiac fibrosis. Most notably, it is characterized by a significant change in the concentration and volume fraction of collagen I, a disproportionate deposition of collagen subtypes, and a disturbed ECM network arrangement, which directly affect the systolic and diastolic functions of the heart. Immune cells that reside within or infiltrate the myocardium, including macrophages, play important roles in fibroblast activation and consequent ECM remodeling. Through both direct and indirect connections to fibroblasts, monocyte-derived macrophages and resident cardiac macrophages play complex, bidirectional, regulatory roles in cardiac fibrosis. In this review, we discuss emerging interactions between fibroblasts and macrophages in physiology and pathologic conditions, providing insights for future research aimed at targeting macrophages to combat cardiac fibrosis.

Rationale: The adult cardiac extracellular matrix (ECM) is largely comprised of type I collagen. In addition to serving as the primary structural support component of the cardiac ECM, type I collagen also provides an organizational platform for other ECM proteins, matricellular proteins, and signaling components that impact cellular stress sensing in vivo. Objective: Here we investigated how the content and integrity of type I collagen affect cardiac structure function and response to injury. Methods and Results: We generated and characterized Col1a2^−/− mice using standard gene targeting. Col1a2^−/− mice were viable, although by young adulthood their hearts showed alterations in ECM mechanical properties, as well as an unanticipated activation of cardiac fibroblasts and induction of a progressive fibrotic response. This included augmented TGFβ activity, increases in fibroblast number, and progressive cardiac hypertrophy, with reduced functional performance by 9 months of age. Col1a2-loxP-targeted mice were also generated and crossed with the tamoxifen-inducible Postn-MerCreMer mice to delete the Col1a2 gene in myofibroblasts with pressure overload injury. Interestingly, while germline Col1a2^−/− mice showed gradual pathologic hypertrophy and fibrosis with aging, the acute deletion of Col1a2 from activated adult myofibroblasts showed a loss of total collagen deposition with acute cardiac injury and an acute reduction in pressure overload-induce cardiac hypertrophy. However, this reduction in hypertrophy due to myofibroblast-specific Col1a2 deletion was lost after 2 and 6 weeks of pressure overload, as fibrotic deposition accumulated. Conclusions: Defective type I collagen in the heart alters the structural integrity of the ECM and leads to cardiomyopathy in adulthood, with fibroblast expansion, activation, and alternate fibrotic ECM deposition. However, acute inhibition of type I collagen production can have an anti-fibrotic and anti-hypertrophic effect.

The endoplasmic reticulum membrane protein complex (EMC) is an evolutionarily conserved multi‐subunit complex. Due to its essential roles in protein biogenesis and quality control, the EMC has attracted considerable attention in recent years. In this review, we systematically explore the functions and disease‐associated regulatory mechanisms of the EMC across various organ systems. We highlight the lung as a paradigmatic model for illustrating the ‘molecular switch’ function of EMC shaped by spatiotemporal and cell‐type‐specific contexts. Dysfunction of EMC contributes to pathologies and cancers of diverse organs, positioning EMC subunits as potential biomarkers and therapeutic targets. Despite considerable progress, our understanding of the molecular underpinnings of EMC in health and disease remains far from complete. Future efforts should aim to unravel the regulatory networks centered on EMC to harness their potential for cross‐disease therapy development.

Background: Cardiovascular disease (CVD) remains the leading cause of global mortality, with myocardial fibrosis characterized by excessive extracellular matrix (ECM) deposition representing a common endpoint associated with progressive cardiac dysfunction. While studies in animal models of heart disease suggest that preventing or reducing fibrosis can antagonize negative ventricular remodeling, current therapeutic strategies remain clinically limited and ineffective, in part due to an incomplete understanding of the multifactorial nature of the fibrotic process. Methods and Results: We employed artificial intelligence (AI) trained from 6,528 cardiac fibrosis publications over the past decade, which suggested 10 nodal signaling pathways underlying the fibrotic process. Single-cell RNA sequencing was used to quantify pathway activities across mouse models and clinical samples encompassing acute and chronic cardiac injury. Dynamic enrichment analysis revealed 2 critical pathways involved in acute myocardial infarction (MI) injury driven temporally-regulated fibrosis whereby Janus kinase - Signal transducer and activator of transcription (JAK-STAT) signaling peaked early (day 7) while transforming growth factor-β (TGF-β) pathway activity peaked mid-phase (day 14). With more chronically-driven fibrosis, JAK-STAT signaling again emerged, which this time was persistently active during chronic transverse aortic constriction (TAC) injury. Experimentally, single-cell analysis identified a pathogenic myofibroblast subpopulation characterized by high JAK-STAT signaling and ECM secretion capacity. Fibroblast-specific Jak1/2 gene-deleted mice significantly reduced TAC-induced fibrosis by blocking myofibroblast formation from this subpopulation, although these same mice failed to show attenuated fibrosis following MI injury, suggesting a pathway that would be ideal to therapeutically target for chronic fibrosis without affecting necessary acute scar formation. Indeed, based on the predictive AI driven algorithm, a temporal inhibitory strategy was generated for JAK-STAT and TGF-β that permitted compensatory scar formation while more effectively preventing progressive fibrosis and worsened cardiac function versus either singular pathway or chronic antagonism. Conclusion: Here we employed the wealth of past signaling pathway data underlying cardiac fibrosis to train an AI model, which suggested an optimized approach of inhibiting 2 nodal signaling pathways but with differential timing as a more effective therapeutic strategy that reduces pathologic cardiac fibrosis without negatively impacting compensatory fibrotic activity with acute MI injury. The therapeutic approach involves altering the timing of JAK-STAT signaling blockade with ruxolitinib (RUX) in combination with delayed and temporary TGF-β signaling inhibition post MI injury with pirfenidone (PFD).