Biology subjects

Marcho, L. M.

Publications and source records attributed to Marcho, L. M..

3 recordsLinked to original sources

bioRxiv2026

Sertad4 regulates pathological cardiac remodeling.

Cardiac fibrosis driven by persistent myofibroblast activation is a major contributor to adverse ventricular remodeling and heart failure. Bromodomain and extra-terminal domain (BET) inhibition reduces fibrosis and hypertrophy in preclinical models, but direct targeting of the BET co-activator BRD4 is limited by family homology and potential systemic toxicity. Sertad4 (SERTA domain containing protein 4) is a BRD4-dependent gene induced in activated cardiac fibroblasts, yet its role in cardiac pathology is unknown. Here, we examined Sertad4 expression and function in human heart failure and in murine myocardial infarction (MI). SERTAD4 protein was increased in left ventricular tissue from heart failure patients compared with non-failing controls. In Sertad4/LacZ reporter mice, MI triggered strong Sertad4 activation localized to the infarct scar and border zone, with minimal expression in remote myocardium; single-nucleus RNA sequencing further demonstrated that Sertad4 expression is predominantly fibroblast-restricted and significantly upregulated after MI. To test causality, we subjected global Sertad4 knockout mice to 28-day left anterior descending coronary artery ligation. Sertad4 deletion attenuated post-MI remodeling, reduced hypertrophy and ventricular dilation, and preserved systolic function. Consistent with improved structure and function, knockout hearts exhibited reduced cardiomyocyte cross-sectional area and decreased expression of fibrosis and hypertrophy associated genes. Together, these findings identify Sertad4 as a fibroblast enriched regulator of pathological remodeling and suggest that targeting Sertad4 may offer a more cell type-selective alternative to direct BET/BRD4 inhibition for limiting cardiac fibrosis and progression to heart failure

physiology↗

bioRxiv2024

Potent Estrogen Receptor β Agonists with Inhibitory Activity In Vitro, Fail to Suppress Xenografts of Endocrine-Resistant Cyclin-dependent Kinase 4/6 inhibitor-Resistant Breast Cancer Cells

ObjectiveSeventy percent of newly diagnosed breast cancers are estrogen receptor- positive and HER2/neu negative [1]. First-line treatments incorporate endocrine therapy and cyclin-dependent kinase 4/6 inhibitors [2]. However, therapy resistance occurs in most patients [3-5]. Hence, there is an urgent need for effective second-line treatments. We previously showed that the potent estrogen receptor-{beta} agonists, OSU-ERb-12 and LY500307, synergized with the selective estrogen receptor modulator, tamoxifen, in vitro. Furthermore, we showed that these compounds inhibited endocrine-resistant and cyclin-dependent kinase 4/6-inhibitor-resistant estrogen receptor -positive cell lines in vitro [6]. Here, we used fulvestrant- and abemaciclib-resistant T47D-derived cell line xenografts to determine the efficacy of the combination of OSU-ERb-12 and LY500307 with tamoxifen in vivo. ResultsDespite efficacy in vitro, treatments failed to reduce xenograft tumor volumes. Hence, we conclude that this treatment strategy lacks direct cancer cell-intrinsic cytotoxic efficacy in vivo.

cancer biology↗

bioRxiv2022

Molecular signature of RV cardiac remodeling associated with Polymerase Gamma mutation

Aging is associated with metabolic dysfunction and metabolic dysfunction accelerates the course of aging. This is well illustrated by aging-like phenotypes displayed in the Polymerase Gamma mutant mouse. Here, a key residue of the mitochondrial DNA polymerase is mutated (D257A) which hinders proof reading capacity, resulting in mitochondrial DNA mutation and instability. Given known cardiac phenotypes in the POLG mutant mouse, we sought to characterize the course of cardiac dysfunction in the POLG mutant to guide future intervention studies. Including both male and female animals allowed interrogation of sex-specific responses to severe metabolic dysfunction. We also conducted RNA-seq analysis on cardiac right ventricles to broadly identify mechanisms engaged by severe metabolic dysfunction that are associated with RV pathology. Several interesting sex differences were noted. Specifically, female POLG mutants died earlier than male POLG mutants and LV chamber diameters were impacted earlier in females than males. Moreover, male POLG mutants showed LV wall thinning while female POLG mutant LV walls were thicker. Both males and females displayed significant RV hypertrophy. Finally, RNA-seq analysis of the RV tissue indicated that POLG mutation significantly impacted canonical pathways associated with inflammation, fibrosis, and heart failure. Comparison of this RNA-seq dataset with other publically available datasets highlight 1) strong conservation among downregulated genes in models of accelerated cardiac aging, 2) the potential involvement of the mitochondrial unfolded protein response in the POLG mutant, and 3) the ability of zinc dependent HDAC inhibition to rescue the expression of genes downregulated in accelerated cardiac aging.

pathology↗