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CR is accompanied by activation of the innate immune response, with NLRP3 inflammasome emerging as a key player in morphological and functional changes. However, the mechanisms underlying NLRP3 inflammasome assembly and activation in the heart upon beta\u2010adrenergic overactivation remain poorly understood. This study aims to investigate the temporal profile of NLRP3 inflammasome activation and its upstream signaling P2X7\u2010NEK7 in isoproterenol (ISO)\u2010induced CR.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Wild\u2010type (WT), NLRP3 knockout (NLRP3\u2010KO), and P2X7\u2010KO male mice were treated with ISO (60\u2009mg\/kg) for 1\u2009h, 12\u2009h, 24\u2009h, or 14\u2009days. Cardiac function was assessed by echocardiography and plethysmography. Cardiac hypertrophy and fibrosis were evaluated by histology. Fibrosis markers and cytokines gene expression were analyzed by quantitative PCR. Protein expression was evaluated by Western Blotting. Inflammasome assembly was confirmed by ASC speck immunofluorescence.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>WT mice showed a rapid activation of NLRP3 inflammasome in the heart up to 12\u2009h from ISO administration, evidenced by increased NLRP3, ASC speck, Caspase\u20101, and IL\u20101\u03b2. ISO treatment for 12\u2009h also increased P2X7 and NEK7. NLRP3\u2010KO mice were protected from ISO\u2010induced fibrosis and impairment of LV relaxation as well as the Caspase\u20101 activation and cytokines production. NEK7, NLRP3 activation, and fibrosis were prevented in P2X7\u2010KO. NLRP3 deletion did not affect ISO\u2010induced cardiac hypertrophy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings suggest that the NLRP3 inflammasome is activated by the P2X7\u2010NEK7 pathway in the early stage of beta\u2010adrenergic insult, driving ISO\u2010induced cardiac fibrosis and inflammation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/apha.70280","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T04:15:23Z","timestamp":1784088923000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>P2X7<\/scp>\n                    \u2010\n                    <scp>NEK7<\/scp>\n                    \u2010\n                    <scp>NLRP3<\/scp>\n                    Axis Drives Cardiac Inflammation and Fibrosis in Isoproterenol\u2010Induced 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