Elucidating the role of LARP6 in cardiovascular remodeling
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Heart failure remains the leading cause of death in the United States, and always progresses despite currently available treatments and therapeutics. Of note, structural remodeling of the heart precedes the onset of overt symptoms that diminish a patient's quality of life. Many factors contribute to the adverse remodeling and dysfunction observed in heart failure. Of note, obesity, excess sympathetic drive, elevated angiotensin II and aldosterone signaling, and fluid overload create a distinct milieu of cardiac stressors. To compensate, the heart undergoes a period of necessary structural remodeling. However, chronic/excess remodeling disrupts tissue homeostasis and creates an environment that can exacerbate cardiac dysfunction. Therefore, identifying novel, effective therapeutic targets that prevent structural cardiac remodeling and delay the appearance of symptoms is of immense importance. One such molecular target is the La ribonucleoprotein 6, translational regulator (LARP6), which is an mRNA binding protein described for its contributions to fibrotic remodeling. This is achieved through the interaction between LARP6 and the 5' stem loop (5'SL) of collagen I and III mRNA, which increases their half-life and initiates their translation. However, the role of LARP6 in cardiac remodeling has yet to be described. To elucidate its role in cardiovascular remodeling, we genetically manipulated the function of LARP6 in two mouse models and exposed them to clinically relevant cardiac stressors. For the first aim, we utilized the 5'SL mutant mice which possess a mutation within the 5'SL of collagen I transcripts that prevent LARP6 from binding and is reported to decrease fibrotic remodeling. This study was conducted in response to high fat high sucrose (HFHS) feeding in male mice for 28 weeks. Endpoint cardiac assessment revealed increased diastolic dysfunction in WT mice fed a HFHS diet, which was prevented by the 5'SL mutation. Interestingly, fibrosis was not induced by the diet, therefore the protective effect of the 5'SL mutation was mediated through collagen independent effects. To increase focus on the role of LARP6 in cardiac fibrosis, we used a model of Ang II infusion (1000 ng/kg/min) to induce hypertension and cardiac remodeling. This second aim was conducted in male 5'SL mice. Ang II infusion significantly increased blood pressure, cardiac hypertrophy, and fibrosis remodeling in both WT and 5'SL mice. Therefore, in contrast to published data in different organs, LARP6 is dispensable in hypertension-induced fibrotic remodeling. Our final aim was to investigate the role of LARP6 within cardiomyocytes, a cell type not typically associated with fibrotic remodeling. To do this, we generated a transgenic mouse line overexpressing LARP6 in a cardiomyocyte-specific manner. We performed baseline longitudinal studies on male and female mice from 16-40 weeks of age. During this time, WT and LARP6 Tg mice were assessed for changes in blood pressure via tail-cuff plethysmography, as well as cardiac function and cardiac morphology by magnetic resonance imaging (MRI). At 40 weeks of age, mice were euthanized and tissue collected for additional molecular assays. We found that the LARP6 transgenic mice had increased Larp6 gene expression and protein expression localized to cardiomyocytes within the heart. Further, this increase in baseline LARP6 was associated with -increased ColIa1 gene expression, and significantly increased fibrotic remodeling at 40 weeks of age as assessed by picrosirius red (PSR) staining. However, MRI revealed that there were no significant differences in baseline cardiac function. Therefore, we wanted to challenge these mice with hypertensive insult. We expected that the male and female LARP6 Tg mice would have exacerbated cardiac fibrosis and dysfunction with Ang II infusion (1000 ng/kg/min). Unexpectedly, LARP6 prevented the Ang II-mediated systolic dysfunction that was observed in WT mice. Further, LARP6 prevented Ang II-induced interstitial, but not perivascular, fibrosis. This reduction in interstitial fibrosis was associated with reduced myofibroblasts activation as assessed by the number of interstitial cells expressing periostin. RNA sequencing revealed widespread changes to the cardiac transcriptome in response to LARP6 overexpression. Overall, cardiomyocyte-derived LARP6 is a multifunctional protein that exerts cardioprotective effects in the setting of hypertension.
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Ph. D.