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In this study, we used IL-12\u03b2 knockout (KO) mice to test the hypothesis that genetic inhibition of IL-12\u03b2 would attenuate transverse aortic constriction (TAC)-induced cardiac inflammation, hypertrophy, and dysfunction, as well as the consequent lung remodeling. IL-12\u03b2 KO in male and female mice significantly attenuated TAC-induced cardiac dysfunction as evidenced by improved left ventricular (LV) ejection fraction and fractional shortening. IL-12\u03b2 KO also significantly ameliorated the TAC-induced increase of LV weight, left atrial weight, lung weight, right ventricular (RV) weight, and their ratios to body weight or tibial length in male and female mice. In addition, IL-12\u03b2 KO significantly attenuated TAC-induced LV leukocyte infiltration, cardiomyocyte hypertrophy, fibrosis, and the consequent lung inflammation and remodeling. Moreover, IL-12\u03b2 KO reduced TAC-induced alterations of LV gene profile associated with inflammation and fibrosis, as shown by bulk LV RNA sequencing. Furthermore, we found that IL-12\u03b2 KO significantly attenuated TAC-induced LV accumulation of multiple immune cell subsets, activation of CD4\n                  <jats:sup>+<\/jats:sup>\n                  and CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells, and the percentage of central memory CD4\n                  <jats:sup>+<\/jats:sup>\n                  and CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells in the cardiac drainage lymph nodes. Finally, IL-12\u03b2 KO mice showed significantly reduced IFN\u03b3\n                  <jats:sup>+<\/jats:sup>\n                  CD8\n                  <jats:sup>+<\/jats:sup>\n                  and CXCR3\n                  <jats:sup>+<\/jats:sup>\n                  CD8\n                  <jats:sup>+<\/jats:sup>\n                  T cells in the drainage lymph nodes as compared with WT after TAC. These findings collectively demonstrate that IL-12\u03b2 plays a critical role in systolic overload-induced LV inflammation, remodeling, and dysfunction, likely through cardiac immune cell infiltration.\n                <\/jats:p>","DOI":"10.1101\/2025.09.05.674485","type":"posted-content","created":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T12:25:18Z","timestamp":1757593518000},"source":"Crossref","is-referenced-by-count":0,"title":["Genetic inhibition of IL-12\u03b2 suppresses systolic overload-induced cardiac inflammation and heart failure development"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-4042-836X","authenticated-orcid":false,"given":"Umesh","family":"Bhattarai","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8266-5895","authenticated-orcid":false,"given":"Xiaochen","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ziru","family":"Niu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lihong","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dongzhi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heng","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian-Xiong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0131-5253","authenticated-orcid":false,"given":"Joshua S.","family":"Speed","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John S.","family":"Clemmer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John E.","family":"Hall","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yingjie","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025091304100492000_2025.09.05.674485v1.1","doi-asserted-by":"publisher","DOI":"10.1161\/CIR.0000000000001209"},{"key":"2025091304100492000_2025.09.05.674485v1.2","doi-asserted-by":"publisher","DOI":"10.1161\/HYPERTENSIONAHA.111.186072"},{"key":"2025091304100492000_2025.09.05.674485v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2013.10.033"},{"issue":"4","key":"2025091304100492000_2025.09.05.674485v1.4","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1007\/s12265-019-9864-y","article-title":"Profound Increase of Lung Airway Resistance in Heart Failure: a Potential Important Contributor for Dyspnea","volume":"12","year":"2019","journal-title":"J Cardiovasc Transl Res"},{"key":"2025091304100492000_2025.09.05.674485v1.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2017.01.051"},{"key":"2025091304100492000_2025.09.05.674485v1.6","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.117.031608"},{"key":"2025091304100492000_2025.09.05.674485v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0735-1097(96)00268-9"},{"key":"2025091304100492000_2025.09.05.674485v1.8","doi-asserted-by":"crossref","unstructured":"Niazy N , Mrozek L , Barth M , Immohr MB , Kalampokas N , Saeed D , et al. 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