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Probing the CaV1.2 interactome in heart failure identifies a positive modulator of inotropy and lusitropy

ABSTRACT: Maladaptive changes in the function, expression and localization of proteins involved in calcium-handling worsen the impaired contractility of systolic heart failure (HF). Standard proteomics techniques require cell lysis and so are unable to characterize changes specific to the critical sub-cellular domain bounded by the T-tubule and the sarcoplasmic reticulum, known as the cardiac dyad. Traditional approaches are also less likely to capture low-affinity protein-protein interactions on lipid membranes. To improve our understanding of heart failure pathophysiology, we applied proximity proteomics to cardiac dyads of mice with ischemic cardiomyopathy.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Heart, Cardiac Muscle Myoblast

DISEASE(S): Heart Failure

SUBMITTER: Marian Kalocsay

LAB HEAD: Jared Kushner

PROVIDER: PXD063582 | Pride | 2026-04-15

REPOSITORIES: Pride

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			Action	DRS
	350831_SM_11plx_1_Fr1_1_4h_L06806.mzid	Mzid
	350833_SM_11plx_1_Fr1_2_4h_L06807.mzid	Mzid
	350835_SM_11plx_1_Fr1_3_4h_L06808.mzid	Mzid
	351555_SM_11plx_1_Fr2_4h_L06809_20180725220323.mzid	Mzid
	351557_SM_11plx_1_Fr4_L06811.mzid	Mzid

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Project description:VEGF family members are important regulators of vascular functions. Promoting VEGFA signalling in aged mice has been shown to delay various aging phenotypes and extend the survival of aged mice. Although there is profound knowledge on functions of VEGFA, VEGFB has not been investigated in the context of cardiac aging. Our RNA data of aged mouse hearts revealed significant downregulation of Vegfb in the heart, specifically in endothelial cells and cardiomyocytes, while VEGFB expression was reduced in endothelial cells, fibroblasts and cardiomyocytes in aged human hearts. By contrast, VEGFB expression was exclusively reduced in cardiomyocytes of patients with cardiac hypertrophy. Hence, we investigated whether Vegfb gene therapy can revert age-dependent cardiac pathologies. We overexpressed Vegfb186, the soluble VEGFB isoform, via AAV9 vector transduction into 18-month-old C57Bl/6J male mice. AAV9-Vegfb treatment prevented progression age-related diastolic dysfunction and decreased cardiac fibrosis. We further found a rescue of aging-related left ventricular denervation in the hearts of AVV9-Vegfb treated old mice which was associated with an increase in heart rate variability. However, heart to body weight ratio and cardiomyocyte hypertrophy were increased in the AAV9-Vegfb treated mouse hearts, without alteration of cardiac systolic or diastolic function. Histological and transcriptomic analyses revealed that VEGFB186 induces compensatory cardiac hypertrophy which was accompanied by a rescued length-width-ratio, reduced fibrosis and the absence of cardiac inflammation. Cardiac single-nuclei RNA sequencing further suggested that AAV9-Vegfb treatment affects cardiac hypertrophy putatively via STAT3 which was validated in vitro. In conclusion, our data reveals that Vegfb overexpression partially reverses pathological alterations in the aging heart. Despite the overall improvement of the age-related cardiac phenotype, the AAV9-Vegfb-mediated induced cardiac hypertrophy which might reflect protective hypertrophy.

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Probing the CaV1.2 interactome in heart failure identifies a positive modulator of inotropy and lusitropy

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