Key result
SRPK inhibitor MSC1186 reduces e/e' ratio by ~8 points, improving HFpEF diastolic dysfunction in mice.
Why the study?
Heart failure with preserved ejection fraction is characterized by impaired diastolic function, but the impact of TPM1 alternative splicing in HFpEF remains unclear.
Does the alternative splicing of TPM1 mediated by SRPK3 drive cardiac diastolic dysfunction and myofiber disarray in HFpEF?
Does the alternative splicing of TPM1 mediated by SRPK3 drive cardiac diastolic dysfunction and myofiber disarray in HFpEF?
SRPK3-mediated alternative splicing of TPM1 exon 9a drives myofilament disorder and diastolic dysfunction in HFpEF, identifying a novel mechanism and potential therapeutic target for this condition.
Answers are grounded in this paper and cite their sources.
SRPK inhibition may target diastolic dysfunction in HFpEF; hypothesis-generating from animal data and leaves open human translation.
BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) has become the most prevalent type of heart failure, a condition characterized by impaired diastolic function and elevated left ventricular stiffness. TPM1 (tropomyosin 1), a crucial part of the thin filament in cardiomyocytes, has multiple alternative exons. However, the impact of TPM1 alternative splicing (AS) in HFpEF remains unclear. METHODS: We examined cardiac myofiber disarray in HFpEF using transmission electron microscopy. Nanoindentation was used to detect myocardial compliance. Using genetically engineered (adenovirus-associated virus serotype 9) mouse models and human pluripotent stem cell-derived cardiomyocytes, we investigated the role of TPM1 isoforms and its upstream SRPK3 (serine/arginine rich protein kinase 3). Subsequently, the underlying mechanisms were investigated using RNA pulldown, mass spectrometry, AS analysis, and other molecular techniques. RESULTS: We identified unique myofilament disorders in HFpEF and observed upregulation of the TPM1b isoform, which skips exon 9a through AS, in both patients with HFpEF and mouse models. Cardiomyocyte-specific overexpression of distinct TPM1 isoforms showed that TPM1b (without exon 9a) exacerbated HFpEF phenotypes in mice and human pluripotent stem cell-derived cardiomyocytes. Furthermore, we found that the splicing kinase SRPK3 mediates the AS of TPM1 exon 9a. Cardiomyocyte-specific overexpression of SRPK3 induced myofiber disarray and diastolic dysfunction, whereas SRPK3 knockdown ameliorated these pathological phenotypes. Supplementation with TPM1 containing exon 9a partially rescued the diastolic dysfunction under conditions of SRPK3 overexpression. Preventive intervention experiments demonstrated that inactivating SRPK3 can alleviate diastolic dysfunction in the HFpEF mouse model. CONCLUSIONS: AS of TPM1 exon 9a is a critical pathogenic mechanism in myofilament disorder and diastolic dysfunction in HFpEF, which is dependent on the upstream splicing kinase SRPK3. SRPK3 may represent a novel therapeutic target for HFpEF.
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Chen et al. (2026) studied Heart failure with preserved ejection fraction (HFpEF). MSC1186 (SRPK inhibitor) vs. Solvent (vehicle control) was evaluated on Cardiac diastolic dysfunction measured by e/e' ratio (early transmitral flow velocity to mitral annular early diastolic velocity). The SRPK inhibitor MSC1186 significantly attenuated cardiac diastolic dysfunction in a mouse model of HFpEF, reducing the e/e' ratio from 33.70 to 25.32.
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