Biology subjects

Telljohann, R.

Publications and source records attributed to Telljohann, R..

3 recordsLinked to original sources

bioRxiv2022

A Remarkable Adaptive Paradigm Of Heart Performance And Protection Emerges In Response To The Constitutive Challenge Of Marked Cardiac-Specific Overexpression Of Adenylyl Cyclase Type 8

Adult mice with cardiac-specific overexpression of adenylyl cyclase (AC) type VIII (TGAC8) adapt to an incessantly increased cAMP-induced cardiac workload ([~]30% increases in heart rate, ejection fraction and cardiac output) for up to a year without signs of heart failure or excessive mortality. Here we show that despite markedly increased cardiac work, classical cardiac hypertrophy markers were absent in TGAC8, total left ventricular (LV) mass was not increased: a reduced LV cavity volume in TGAC8 was encased by thicker LV walls harboring an increased number of small cardiac myocytes and a network of small interstitial non-cardiac myocytes, manifesting increased proliferation markers and compared to WT. Protein synthesis, proteosome activity, autophagy, and Nrf-2, Hsp90, ACC2 protein levels were increased in TGAC8, but LV ATP and phosphocreatine levels in vivo did not differ by genotype. 2,323 transcripts and 2,184 proteins identified in unbiased omics analyses, spanning a wide array of biological processes and molecular functions in numerous cellular compartments differed in TGAC8 vs WT; and over 250 canonical signaling pathways characteristic of adaptive survival circuitry of cancers, including PI3K and growth factor signaling, cytokine and T cell receptor signaling, immune responses, ROS scavenging, proliferation, protection from apoptosis, and nutrient sensing, were activated in TGAC8; and compared to WT there was a shift from fatty acid oxidation to increased aerobic glycolysis in the context of increased utilization of the pentose phosphate shunt and nucleotide synthesis. Thus, the adaptive paradigm, that becomes activated in the LV of TGAC8 in response to severe chronic, intense AC/PKA/Ca2+ signaling embodies many hallmarks of cancer.

physiology↗

bioRxiv2021

The Interaction of Angiotensin II and Milk Fat Globule Epidermal Growth Factor VIII in Proinflammatory Arterial Remodeling

BackgroundAngiotensin II (Ang II) and milk fat globule-epidermal growth factor VIII (MFG-E8) are involved in age-associated arterial remodeling; however, the inflammatory role of MFG-E8 in Ang II associated arterial remodeling with aging remains unknown. Methods and ResultsIn this study, 30-week-old MFG-E8 knock out (KO) and age-matched wild-type (WT) mice were infused with Ang II or saline. After infusion the with Ang II, the aortic molecular, cellular, and structural remodeling were observed in mice and compared to those infused with saline, but these effects were dependent on the expression of MFG-E8: (1) In the WT mice, Ang II infusion substantially increased intimal-medial thickness, elastic lamina degradation, collagen deposition, and the proliferation of VSMCs; in contrast, in the KO mice, these effects were significantly reduced; (2) In the WT mice, Ang II treatment significantly increased the activation and expression of MMP2, TGF-{beta}1, and its downstream signaling molecule p-SMAD2, and collagen type I production, however, in the KO mice, these molecular effects were significantly reduced; (3) In the WT mice, Ang II treatment increased inflammatory p-NF-{kappa}B p65, MCP1, TNF-, ICAM1, and VCAM1 molecular expression, while conversely, in the KO mice, no significant inflammatory changes were found; (4) Importantly, compared to untreated control mice with a wide range of age from 4-96 weeks, Ang II infused "younger" mice produced an "older" arterial inflammatory phenotype, which was alleviated by MFG-E8 deficiency. ConclusionsMFG-E8 mediates Ang II associated arterial inflammatory remodeling. Targeting MFG-E8 is a novel molecular approach to curb adverse arterial remodeling during aging and hypertension. CLINICAL PERSPECTIVEO_ST_ABSWhat Is New?C_ST_ABS* Both Ang II and MFG-E8 increases are involved in proinflammatory arterial remodeling mediating the molecular, cellular and tissue events in aging and hypertension. * MFG-E8 is essential for Ang II induced and age-associated adverse arterial remodeling via the increase of proinflammation, intimal medial thickening, elastin fragmentation, collagen deposition, and VSMC proliferation. What Are the Clinical Implications?Since MFG-E8 mediates Ang II induced proinflammation in arterial wall remodeling in aging and hypertension, targeting MFG-E8 is a potential molecular approach to curb inflammatory arterial remodeling, maintaining the health of the vascular system during aging and hypertension.

pathology↗

bioRxiv2020

MFG-E8 Signaling Promotes Elastolysis and Calcification in the Aging Aortic Wall

Milk fat globule-EGF factor 8 (MFG-E8) protein increases with age and is mainly secreted by vascular smooth muscle cells in the arterial wall. Here, we investigated the role of MFG-E8 signaling during proinflammation, elastolysis, fibrosis, and calcification within the aging arterial wall. In vivo studies indicated that (1) Elastic lamina breaks collagen deposition and calcium-phosphorus products were markedly increased in the aging arterial wall of rats; (2) MFG-E8 protein abundance was markedly increased while intact tropoelastin (TPELN), an element of repair of the elastic fibers, was markedly decreased in the aging arterial wall of rats; (3) The absence of MFG-E8 markedly alleviated age-associated increases in elastic lamina breaks, collagen deposition and calcium-phosphorus products in mice; and (4) MFG-E8 deficiency significantly decreased age-associated increases in matrix metalloproteinase type II (MMP-2) activation, alkaline phosphatase, and runt-related transcription factor 1 (Runx1) expression in the aortic walls of mice. The in vitro studies demonstrated that (1) treating either young or old rat VSMCs with recombinant human MFG-E8 protein (rhMFG-E8) significantly reduced TPELN levels while MFG-E8 gene silencing significantly increased TPELN levels; (2) rhMFG-E8 treatment activated MMP-2 levels in both young and old VSMCs; and (3) MMP-2 bound to and cleaved TPELN secreted from VSMCs. Thus, these findings suggest that MFG-E8 signaling promotes age-associated adverse structural remodeling, including elastolysis, fibrosis, and calcification; however, MFG-E8 deficiency markedly mitigates these adverse effects in mice.

pathology↗