Biology subjects

Samuelsson, A.-M.

Publications and source records attributed to Samuelsson, A.-M..

3 recordsLinked to original sources

bioRxiv2026

Regulation of the Balance between Concentric and Eccentric Cardiac Hypertrophy by a CDC14A-KMT5A Signaling Pathway

BackgroundDepending upon the type of pathological stress, the heart undergoes concentric or eccentric remodeling. This structural change is associated with diastolic and/or systolic ventricular dysfunction reflecting differentially altered cardiomyocyte morphology, ultrastructure, metabolism, contractility, and survival, as well as interstitial myocardial fibrosis. Despite an association of both concentric and eccentric remodeling with heart failure and sudden death, the molecular mechanisms resulting in abnormal cardiac geometry remain poorly understood. A better understanding of the basic mechanisms conferring these contrasting forms of remodeling should inform novel approaches to preserve normal cardiac structure and function in cardiovascular disease. The protein phosphatase Cell Division Cycle 14A (CDC14A) and its substrate the lysine methyltransferase KMT5A are identified herein as key regulators of the balance between concentric and eccentric pathological cardiac remodeling. MethodsThe regulation of adult rat ventricular myocyte morphology by CDC14A and KMT5A was studied in vitro following gain and loss of function by expression of wild-type and mutant proteins and RNA interference (RNAi). Epigenomic regulation by KMT5A was studied by mapping histone 4 lysine 20 mono-methylation (H4K20me1) modified chromatin sites and correlating them with gene transcription. Regulation of pathological cardiac remodeling in vivo was demonstrated by CDC14A and KMT5A RNAi using adeno-associated virus (AAV) mediated cardiomyocyte-specific small hairpin RNA (shRNA) expression in mice. ResultsCDC14A inhibited the growth in width of cultured adult myocytes stimulated by -adrenergic receptor activation or by serum response factor. KMT5A was downregulated by CDC14A in cardiomyocytes and was required for myocyte growth in width. -adrenergic stimulation of KMT5A-dependent H4K20 mono-methylation across transcription units correlated with regulation of gene transcription. Accordingly, AAV-expressed KMT5A shRNA induced eccentric remodeling and cardiac dysfunction in wild-type mice. Conversely, expression of Cdc14A shRNA improved systolic function and cardiac structure and inhibited pathological gene expression in the Tpm1 E54K mouse with Dilated Cardiomyopathy. ConclusionsCDC14A-KMT5A-dependent epigenomic regulation of gene transcription constitutes a molecular switch that determines concentric versus eccentric cardiac remodeling. These findings identify CDC14A as a potential therapeutic target for the treatment of dilated cardiomyopathy and other forms of heart failure with reduced ejection fraction. Clinical PerspectiveO_ST_ABSWhat is newC_ST_ABSO_LIA function is identified for the first time for the protein phosphatase CDC14A in the heart, regulation of cardiomyocyte morphology and overall cardiac geometry in pathological cardiac remodeling. C_LIO_LIThe lysine methyltransferase KMT5A is shown to mediate the effects of CDC14A in the adult cardiomyocyte by regulating H4K20 mono-methylation, such that reduced KMT5A expression promotes a phenotype resembling Dilated Cardiomyopathy. C_LIO_LIH4K20me1 epigenomic modification is identified as a regulator of cardiac structure and function. C_LI Clinical implicationsO_LICDC14A loss of function experimentation in vivo, resulting in improved cardiac structure and function in a mouse model of Dilated Cardiomyopathy, suggests that CDC14A is a novel therapeutic target for heart failure with reduced ejection fraction. C_LI

cell biology↗

bioRxiv2025

Targeting of CIP4-Calcineurin Signalosomes Improves Cardiac Structure and Function After Myocardial Infarction

BackgroundCalcineurin in a pleiotropic signaling enzyme that promotes pathological cardiac remodeling but also cardioprotection in ischemia-reperfusion injury. In addition, calcineurin inhibitors are immunosuppressants. This pleiotropy has precluded the use of calcineurin inhibitors as treatments for heart failure. Cdc42-interacting protein 4 (CIP4/TRIP10) is an endosomal scaffold protein that organizes a calcium and calcineurin A{beta}2 (CaNA{beta}2) signaling compartment activated by G-protein coupled receptors independently of contractile calcium. CIP4 binds CaNA{beta}2 via the CaNA{beta}-specific N-terminal polyproline (PP) domain. We previously showed that targeting of CIP4-CaNA{beta}2 signalosomes inhibited pathological cardiac hypertrophy and the development of heart failure induced by chronic pressure overload in mice. It is unknown whether CIP4-CaNA{beta}2 signalosomes contribute to cardioprotection and/or cardiac remodeling in ischemic heart disease. MethodsCIP4 conditional knock-out (CKO) mice were studied by echocardiography with strain analysis and histology following ischemia-reperfusion (I/R) injury and permanent left coronary artery (LCA) ligation to induce myocardial infarction. Wildtype C57BL/6NJ mice were transduced with adeno-associated virus (AAV) engineered for cardiomyocyte-specific expression of either a CaNA{beta}2 shRNA to inhibit CaNA{beta}2 expression, a VIVIT peptide to inhibit CaN-NFAT signaling, or a CaNA{beta}2 PP peptide to block CIP4-CaNA{beta}2 binding. AAV-transduced mice were studied by I/R injury. Additional mice were subjected to permanent LCA ligation and subsequently treated with AAV to test the effects of CaN inhibition in chronic ischemic cardiomyopathy. The effects of CaNA{beta}2 PP-GFP expression on primary T-cell activation were studied in vitro. ResultsCIP4 CKO mice and mice expressing the PP anchoring disruptor peptide exhibited preserved cardiac function after I/R injury and decreased infarct size and preserved cardiac function 8 weeks after myocardial infarction by permanent LCA ligation. In contrast, cardiomyocyte-specific depletion of CaNA{beta}2 and VIVIT peptide expression worsened outcome after I/R injury and in chronic ischemic cardiomyopathy. In addition, in contrast to cardiomyocytes, PP-mediated CaNA{beta} anchoring inhibition had no effect on T-cell activation and cytokine expression in vitro. ConclusionsCIP4-CaNA{beta}2 signalosomes promote adverse cardiac remodeling and are not cardioprotective. Proof-of-concept is provided for the treatment of ischemic cardiomyopathy by a PP anchoring disruptor gene therapy. Targeting these complexes may be beneficial in cardiovascular diseases, including ischemic cardiomyopathy and acute myocardial infarction. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LITargeting CIP4, which is a scaffold protein for the phosphatase calcineurin, improves cardiac function in mice after acute myocardial infarction due to ischemia-reperfusion injury and in chronic ischemic cardiomyopathy. C_LIO_LIGene therapy-based expression of a calcineurin A{beta}-derived polyproline peptide, which can compete CIP4-calcineurin binding, is beneficial in acute and chronic myocardial infarction. C_LI What Are the Clinical Implications?O_LIThis study establishes CIP4 signalosomes as a new drug target for the treatment of ischemia-reperfusion injury and chronic pathological cardiac remodeling. C_LIO_LIThis study provides proof-of-concept for a new gene therapy approach to treating acute myocardial infarction and chronic ischemic cardiomyopathy. C_LI

physiology↗

bioRxiv2024

The Unique Role of Intracellular Perinuclear β-Adrenergic Receptors in defining Signaling Compartmentation and Pathological Cardiac Remodeling

The {beta}-adrenergic receptor is a prototypical G-protein coupled receptor that initiates signaling from the plasma membrane. However, active receptors have been detected within intracellular compartments. The functional significance of these intracellular receptors remains unclear, including whether they regulate distinct cellular processes or function independently of plasma membrane receptors. We show using live cell imaging of primary cardiomyocytes that {beta}-adrenergic receptors localized to Golgi apparatus opposing the outer nuclear membrane are sufficient and necessary for the stimulation of cAMP and calcium signaling within a nanometer scale compartment independent of receptors at other sites. Using compartment-specific activators and inhibitors, we show Golgi {beta}-adrenergic receptors associated with the scaffold protein AKAP6{beta} and the outer nuclear membrane protein nesprin-1 are responsible for pathological gene transcription and the induction of cardiomyocyte hypertrophy. The functional significance of Golgi-localized receptors is demonstrated in mice models of cardiomyopathy, providing proof-of-concept for a compartment-specific therapeutic intervention in Dilated Cardiomyopathy.

cell biology↗