Rationale Adoptive transfer of cardiac progenitor cells (CPCs) has entered clinical application despite limited mechanistic understanding of the endogenous response following myocardial infarction (MI). Extracellular matrix (ECM) undergoes dramatic changes after MI and therefore might be linked to CPC-mediated repair. Objective Demonstrate the significance of Fibronectin (Fn), a component of the ECM, for induction of the endogenous CPC response to MI. Methods and Results This report shows that presence of CPCs correlates with expression of Fn during cardiac development and after MI. In vivo, genetic conditional ablation of Fn blunts CPC response measured 7 days after MI through reduced proliferation and diminished survival. Attenuated vasculogenesis and cardiogenesis during recovery was evident at the end of a 12 week follow-up period. Impaired CPC-dependent reparative remodeling ultimately leads to continuous decline of cardiac function in Fn knockout animals. In vitro, Fn protects and induces proliferation of CPCs via β1-Integrin-FAK-Stat3-Pim1 but Akt-independent mechanism. Conclusion Fn is essential for endogenous CPC expansion and repair needed for stabilization of cardiac function after MI.

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In 2019, lung cancer was estimated to be the leading cause of cancer deaths in humans. Polycyclic aromatic hydrocarbons (PAHs) are known to increase the risk of lung cancer. PAHs are metabolized by the cytochrome P450 (CYP)1A subfamily, comprised of the CYP1A1 and CYP1A2 monooxygenases. These enzymes bioactivate PAHs into reactive metabolites that induce mutagenic DNA adducts, which can lead to cancer. Past studies have investigated the role of CYP1A1 in PAH bioactivation; however, the individual roles of each CYP1A enzyme are still unknown. In this investigation, we tested the hypothesis that mice lacking the genes for Cyp1a1 or Cyp1a2 will display altered susceptibilities to PAH-induced pulmonary carcinogenesis. Wild-type (WT), Cyp1a1-null (Cyp1a1-/-), and Cyp1a2-null (Cyp1a2-/-) male and female mice were treated with 3-methylcholanthrene (MC) for cancer initiation and tumor formation studies. In WT mice, CYP1A1 and 1A2 expression was induced by MC. Cyp1a1-/- and Cyp1a2-/- mice treated with PAHs displayed a compensatory pattern, where knocking out one Cyp1a gene led to increased expression of the other. Cyp1a1-/- mice were resistant to DNA adduct and tumor formation, while Cyp1a2-/- mice displayed increased levels of both. UALCAN analysis revealed that lung adenocarcinoma (LUAD) patients with high levels of CYP1A2 expression survive significantly better than patients with low/medium expression. In conclusion, Cyp1a1-/- mice were less susceptible to PAH-induced pulmonary carcinogenesis, while Cyp1a2-/- mice were more susceptible. Additionally, high CYP1A2 expression was found to be protective for LUAD patients. These results support the need to develop novel CYP1A1 inhibitors to mitigate human lung cancer.

Lung cancer is the leading cause of cancer‐related deaths in the United States. Polycyclic aromatic hydrocarbons (PAHs) are a group of chemicals that increase the risk of lung cancer in humans. PAHs induce phase I and II metabolism enzymes through aryl hydrocarbon receptor (AhR)‐ dependent and independent pathways. Cytochrome P450 (CYPs) enzymes are among these phase I enzymes and promote detoxification of PAHs. However, CYP1A1, 1A2, and 1B1, which belong to the CYP1A1 family of enzymes, are also involved in the bioactivation of PAHs, leading to the formation of reactive intermediates that can form mutagenic DNA adducts. In this study, we hypothesized that mice lacking all the genes of the Cyp1 family will be resistant to PAH‐mediated pulmonary carcinogenesis. To test this hypothesis, A/J (WT) and Cyp1a1/1a2/1b1‐triple knockout (Cyp1‐3ko) mice were exposed to 3‐methylcholanthrene (MC; 100 μmol/kg), benzo(a)pyrene (BP; 200 μmol/kg), or corn oil (vehicle) via a single intraperitoneal injection. Liver and lung tissues were harvested at 1, 8, and 15 days post PAH exposure for our short‐term studies. Mice in our tumor study were harvested 36 weeks post PAH exposure for tumor incidence and multiplicity analysis. We found that MC caused significant induction of hepatic CYP1A1/1A2 gene expression in WT but not CYP1‐3KO mice at each time point. MC treatment caused formation of DNA adducts in liver and lung for up to 15 days post MC treatment in both genotypes. However, compared to WT animals, Cyp1‐3ko mice had significantly reduced hepatic DNA adducts on day 15 and up to 95% less pulmonary DNA adducts at 1, 8 and 15 days post MC treatment. In addition to the DNA adduct inhibition, Cyp1‐3ko mice formed 93% less pulmonary tumors compared to their MC treated WT counterparts. The significant reduction in DNA adducts and pulmonary tumors in Cyp1‐3ko mice provide strong evidence of the mechanistic role these enzymes play in PAH‐mediated carcinogenesis. Future studies on the specific role of each of the enzymes of the CYP1A family will be important for the identification of specific targets that could be used in the prevention and/or treatment of lung carcinogenesis in humans exposed to PAHs and other environmental carcinogens.Support or Funding Information1R01ES029382‐01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.