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However, the underlying mechanisms are largely unclear. The functions of Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2 channels are subtly modulated by splicing factor-mediated alternative splicing (AS), but whether and how Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2 channels are alternatively spliced in diabetic heart remains unknown.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Diabetic rat models were established by using high-fat diet in combination with low dose streptozotocin. Cardiac function and morphology were assessed by echocardiography and HE staining, respectively. Isolated neonatal rat ventricular myocytes (NRVMs) were used as a cell-based model. Cardiac Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2 channel functions were measured by whole-cell patch clamp, and intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      concentration was monitored by using Fluo-4 AM.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We find that diabetic rats develop diastolic dysfunction and cardiac hypertrophy accompanied by an increased Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2 channel with alternative exon 9* (Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2\n                      <jats:sub>E9*<\/jats:sub>\n                      ), but unchanged that with alternative exon 8\/8a or exon 33. The splicing factor Rbfox2 expression is also increased in diabetic heart, presumably because of dominate-negative (DN) isoform. Unexpectedly, high glucose cannot induce the aberrant expressions of Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2 exon 9* and Rbfox2. But glycated serum (GS), the mimic of advanced glycation end-products (AGEs), upregulates Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2\n                      <jats:sub>E9*<\/jats:sub>\n                      channels proportion and downregulates Rbfox2 expression in NRVMs. By whole-cell patch clamp, we find GS application hyperpolarizes the current-voltage curve and window currents of cardiac Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2 channels. Moreover, GS treatment raises K\n                      <jats:sup>+<\/jats:sup>\n                      -triggered intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      concentration ([Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      ), enlarges cell surface area of NRVMs and induces hypertrophic genes transcription. Consistently, siRNA-mediated knockdown of Rbfox2 in NRVMs upregulates Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2\n                      <jats:sub>E9*<\/jats:sub>\n                      channel, shifts Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2 window currents to hyperpolarization, increases [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      and induces cardiomyocyte hypertrophy.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      AGEs, not glucose, dysregulates Rbfox2 which thereby increases Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2\n                      <jats:sub>E9*<\/jats:sub>\n                      channels and hyperpolarizes channel window currents. These make the channels open at greater negative potentials and lead to increased [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      in cardiomyocytes, and finally induce cardiomyocyte hypertrophy in diabetes. Our work elucidates the underlying mechanisms for Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2 channel regulation in diabetic heart, and targeting Rbfox2 to reset the aberrantly spliced Ca\n                      <jats:sub>V<\/jats:sub>\n                      1.2 channel might be a promising therapeutic approach in diabetes-induced cardiac hypertrophy.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12933-023-01894-5","type":"journal-article","created":{"date-parts":[[2023,7,6]],"date-time":"2023-07-06T06:01:53Z","timestamp":1688623313000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Dysregulated Rbfox2 produces aberrant splicing of CaV1.2 calcium channel in diabetes-induced cardiac hypertrophy"],"prefix":"10.1186","volume":"22","author":[{"given":"Pengpeng","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongxia","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiange","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Hou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shumin","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miaomiao","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W.C. 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