Biology subjects

Aghajanian, A.

Publications and source records attributed to Aghajanian, A..

3 recordsLinked to original sources

bioRxiv2026

The nuclear receptor ROR-alpha is a critical myogenic regulator of the cardiomyocyte transcriptome, including the alpha-1A adrenergic receptor

AimsWe recently found that the nuclear receptor retinoic acid-related orphan nuclear receptor alpha (ROR) protects against angiotensin II-induced cardiac hypertrophy and promotes cardiomyocyte mitophagy. The underlying molecular basis for these salutary effects remains unclear. MethodsWe used RNA microarrays to profile the cardiac transcriptomes of "staggerer" (RORsg/sg) mice that carry a naturally occurring mutation in the ligand-binding domain of ROR, resulting in a global loss-of-function genetic model. We then used genetic and pharmacologic loss-and-gain of function studies in cultured cardiomyocytes to ascertain whether ROR regulates transcription of Adra1a, the gene that encodes the alpha-1A-adrenergic receptor (1A-AR). ResultsThe absence of functional ROR results in broad transcriptional changes in the heart providing a likely molecular basis for the RORsg/sg cardiac phenotype. In vivo and in vitro studies confirmed that ROR directly regulates Adra1a transcription. This effect is enhanced by hypoxia. ConclusionsCollectively these findings position ROR as a previously unrecognized central regulator of the cardiac myogenic transcriptome and the first recognized transcriptional regulator of Adra1a in cardiomyocytes. Future studies will probe the contribution of ROR-mediated transcriptional regulation of Adra1a to both the response to cardiomyocyte injury and maintenance of circadian biology.

physiology↗

bioRxiv2024

Lymphatic activation of ACKR3 signaling regulates lymphatic response after ischemic heart injury.

2.BackgroundIschemic heart disease is a prevalent cause of death and disability worldwide. Recent studies reported a rapid expansion of the cardiac lymphatic network upon ischemic heart injury and proposed that cardiac lymphatics may attenuate tissue edema and inflammatory mechanisms after ischemic heart injury. Nevertheless, the mechanisms through which hypoxic conditions affect cardiac lymphangiogenesis and function remain unclear. Here, we aimed to characterize the role of the adrenomedullin decoy receptor atypical chemokine receptor 3 (ACKR3) in the lymphatic response following ischemic heart injury. MethodsSpatial assessment of ACKR3 signaling in the heart after ischemic heart injury was conducted using ACKR3-TangoGFP reporter mice. Roles of ACKR3 after ischemic heart injury were characterized in Ackr3{Delta}Lyve1 mice and in cultured human lymphatic endothelial cells (LECs) exposed to hypoxia. ResultsUsing the novel ACKR3-Tango-GFP reporter mice, we detected activation of ACKR3 signaling in cardiac lymphatics adjacent to the site of ischemic injury of left anterior descending artery (LAD) ligation. Ackr3{Delta}Lyve1 mice exhibited better survival and were protected from the formation of acute tissue edema after ischemic cardiac injury. Ackr3{Delta}Lyve1 mice exhibited a denser cardiac lymphatic network after LAD ligation, especially in the injured tissues. Transcriptomic analysis revealed changes in cardiac lymphatic gene expression patterns that have been associated with extracellular matrix remodeling and immune activation. We also found that ACKR3 plays a critical role in the regulating continuous cell-cell junction dynamics in LECs under hypoxic conditions. ConclusionsLymphatic expression of ACKR3 governs numerous processes following ischemic heart injury, including the lymphangiogenic response, edema protection and overall survival. These results expand our understanding of how the heart failure biomarker adrenomedullin, regulated by lymphatic ACKR3, may exert its cardioprotective roles after ischemic cardiac injury.

physiology↗

bioRxiv2020

The nuclear receptor RORα preserves cardiomyocyte mitochondrial function by regulating mitophagy through caveolin-3

Preserving optimal mitochondrial function is critical in the heart, which is the most ATP-avid organ in the body. Recently, we showed that global deficiency of the nuclear receptor ROR in the "staggerer" (RORsg/sg) mouse exacerbates angiotensin II-induced cardiac hypertrophy and compromises cardiomyocyte mitochondrial function. The mechanisms underlying these observations have not been defined. Here we present evidence that ROR regulates cardiomyocyte mitophagy using pharmacological and genetic gain- and loss-of-function tools, including a novel cardiomyocyte-specific ROR knockout mouse. Cardiomyocyte ROR is upregulated by hypoxia and the loss of ROR blunts hypoxia-induced mitophagy and broadly compromises mitochondrial function. We show that ROR is a direct transcriptional regulator of the mitophagy mediator caveolin-3 in cardiomyocytes and that increased expression of ROR increases caveolin-3 abundance and enhances mitophagy. Knockdown of ROR impairs cardiomyocyte mitophagy, but this defect can be rescued by caveolin-3 overexpression. Collectively, these findings reveal a novel role for ROR in regulating mitophagy through caveolin-3 and expand our currently limited understanding of the mechanisms underlying ROR-mediated cardioprotection.

molecular biology↗