Temporal dynamics of cardiac hypertrophic growth in response to pressure overload

Abstract

Hypertension is one of the most important risk factors of heart failure. In response to high blood pressure, the left ventricle manifests hypertrophic growth to ameliorate wall stress, which may progress into decompensation and trigger pathological cardiac remodeling. Despite the clinical importance, the temporal dynamics of pathological cardiac growth remain elusive. Here, we took advantage of the puromycin labeling approach to measure the relative rates of protein synthesis as a way to delineate the temporal regulation of cardiac hypertrophic growth. We first identified the optimal treatment conditions for puromycin in neonatal rat ventricular myocyte culture. We went on to demonstrate that myocyte growth reached its peak rate after 8-10 h of growth stimulation. At the in vivo level, with the use of an acute surgical model of pressure-overload stress, we observed the maximal growth rate to occur at after surgery. Moreover, RNA sequencing analysis supports that the most profound transcriptomic changes occur during the early phase of hypertrophic growth. Our results therefore suggest that cardiac myocytes mount an immediate growth response in reply to pressure overload followed by a gradual return to basal levels of protein synthesis, highlighting the temporal dynamics of pathological cardiac hypertrophic growth. We determined the optimal conditions of puromycin incorporation in cardiac myocyte culture. We took advantage of this approach to identify the growth dynamics of cardiac myocytes in vitro. We went further to discover the protein synthesis rate in vivo, which provides novel insights about cardiac temporal growth dynamics in response to pressure overload.

Chronic activation of hexosamine biosynthesis in the heart triggers pathological cardiac remodeling

“…We first determined whether the HBP enzymes were altered in cultured cardiomyocytes by hypertrophic stimuli in a time course study. Phenylephrine (PE) is an agonist for α1 adrenergic receptor, which is commonly used to stimulate cardiomyocyte hypertrophic growth in vitro [28][29][30] . We isolated and cultured primary neonatal rat ventricular myocytes (NRVMs) from 1 to 2 days old Sprague-Dawley rats as before 9,31 .…”

Lactate Dehydrogenase A Governs Cardiac Hypertrophic Growth in Response to Hemodynamic Stress

“…At the in vivo level, thoracic aortic constriction (TAC) is a commonly used surgical approach to induce pressure overload and trigger cardiac hypertrophic growth ( Hill et al, 2000 ). In response to elevated afterload stress, the heart manifests cardiac hypertrophy to ameliorate ventricular wall stress ( Wang et al, 2017 ). We subjected wild-type C57BL/6 mice to TAC and harvested the heart 1 week later.…”

“…Wild-type male mice or genetically modified animals of 8–10 weeks old were used for thoracic aortic constriction (TAC) surgery as previously described ( Wang et al, 2017 ; Zhang et al, 2019 ). Briefly, mice were anesthetized by intraperitoneal injection of ketamine (100 mg/kg body weight) and xylazine (5 mg/kg body weight).…”

Heart Plasticity in Response to Pressure- and Volume-Overload: A Review of Findings in Compensated and Decompensated Phenotypes

“…Sustained elevated systolic stress via thoracic aortic constriction (TAC) in mice, increases the rate of protein synthesis as soon as 4 days post-op and results in cardiac hypertrophy (Wang et al, 2017) (Figure 2). The putative hypothesis of stress normalization, proposed by Grossman et al (1975), argues that elevations in systolic stress are offset by an increase in wall thickness.…”