Browsing by Author "Shah, Ajay M."

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    NF-κB activation in cardiac fibroblasts results in the recruitment of inflammatory Ly6Chi monocytes in pressure-overloaded hearts
    (American Association for the Advancement of Science, 2021) Abe, Hajime; Tanada, Yohei; Omiya, Shigemiki; Podaru, Mihai-Nicolae; Murakawa, Tomokazu; Ito, Jumpei; Shah, Ajay M.; Conway, Simon J.; Ono, Masahiro; Otsu, Kinya; Pediatrics, School of Medicine
    Heart failure is a major public health problem, and inflammation is involved in its pathogenesis. Inflammatory Ly6Chi monocytes accumulate in mouse hearts after pressure overload and are detrimental to the heart; however, the types of cells that drive inflammatory cell recruitment remain uncertain. Here, we showed that a distinct subset of mouse cardiac fibroblasts became activated by pressure overload and recruited Ly6Chi monocytes to the heart. Single-cell sequencing analysis revealed that a subset of cardiac fibroblasts highly expressed genes transcriptionally activated by the transcription factor NF-κB, as well as C-C motif chemokine ligand 2 (Ccl2) mRNA, which encodes a major factor in Ly6Chi monocyte recruitment. The deletion of the NF-κB activator IKKβ in activated cardiac fibroblasts attenuated Ly6Chi monocyte recruitment and preserved cardiac function in mice subjected to pressure overload. Pseudotime analysis indicated two single-branch trajectories from quiescent fibroblasts into inflammatory fibroblasts and myofibroblasts. Our results provide insight into the mechanisms underlying cardiac inflammation and fibroblast-mediated inflammatory responses that could be therapeutically targeted to treat heart failure.
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    Pkm2 Regulates Cardiomyocyte Cell Cycle and Promotes Cardiac Regeneration
    (American Heart Association, 2020-04-14) Magadum, Ajit; Singh, Neha; Kurian, Ann Anu; Munir, Irsa; Mehmood, Talha; Brown, Kemar; Sharkar, Mohammad Tofael Kabir; Chepurko, Elena; Sassi, Yassine; Gyun, Jae; Lee, Philyoung; Santos, Celio X.C.; Gaziel-Sovran, Avital; Zhang, Guoan; Cai, Chen-Leng; Kho, Changwon; Mayr, Manuel; Shah, Ajay M.; Hajjar, Roger J.; Zangi, Lior; Pediatrics, School of Medicine
    Background: The adult mammalian heart has limited regenerative capacity, mostly attributable to postnatal cardiomyocyte cell cycle arrest. In the last 2 decades, numerous studies have explored cardiomyocyte cell cycle regulatory mechanisms to enhance myocardial regeneration after myocardial infarction. Pkm2 (Pyruvate kinase muscle isoenzyme 2) is an isoenzyme of the glycolytic enzyme pyruvate kinase. The role of Pkm2 in cardiomyocyte proliferation, heart development, and cardiac regeneration is unknown. Methods: We investigated the effect of Pkm2 in cardiomyocytes through models of loss (cardiomyocyte-specific Pkm2 deletion during cardiac development) or gain using cardiomyocyte-specific Pkm2 modified mRNA to evaluate Pkm2 function and regenerative affects after acute or chronic myocardial infarction in mice. Results: Here, we identify Pkm2 as an important regulator of the cardiomyocyte cell cycle. We show that Pkm2 is expressed in cardiomyocytes during development and immediately after birth but not during adulthood. Loss of function studies show that cardiomyocyte-specific Pkm2 deletion during cardiac development resulted in significantly reduced cardiomyocyte cell cycle, cardiomyocyte numbers, and myocardial size. In addition, using cardiomyocyte-specific Pkm2 modified RNA, our novel cardiomyocyte-targeted strategy, after acute or chronic myocardial infarction, resulted in increased cardiomyocyte cell division, enhanced cardiac function, and improved long-term survival. We mechanistically show that Pkm2 regulates the cardiomyocyte cell cycle and reduces oxidative stress damage through anabolic pathways and β-catenin. Conclusions: We demonstrate that Pkm2 is an important intrinsic regulator of the cardiomyocyte cell cycle and oxidative stress, and highlight its therapeutic potential using cardiomyocyte-specific Pkm2 modified RNA as a gene delivery platform.