Biology subjects

Kazmierczak, K.

Publications and source records attributed to Kazmierczak, K..

3 recordsLinked to original sources

bioRxiv2024

Sarcomeric SRX:DRX Equilibrium in Alport and LDLR/P407 Mouse Models of HFpEF.

Cardiac myosin energetic states that regulate heart contractility define interactions of myosin cross-bridges with actin-containing thin filaments have been functionally linked with the pathology of hypertrophic cardiomyopathy (HCM). In particular, the balance between the disordered relaxed (DRX) and super relaxed (SRX) states that correlate respectively with enhanced force and energy conservation significantly determine myocardial performance and energy utilization. Compelling evidence suggests that a balanced SRX and DRX states proportion is a prerequisite for long-term cardiac health. Whereas roles for altered SRX: DRX proportions in HCM have been studied in depth, the mechanics of sarcomeric dysfunction and SRX: DRX proportions have not been reported in models of acquired heart failure (HF) including HF with preserved ejection fraction (HFpEF). Here, we quantified SRX andDRX myosin populations in two mouse models of HFpEF, including Alport and LDLR/P407 mice that represent cardiorenal/hypertensive and cardiometabolic/hyperlipidemic mouse models of HFpEF, respectively. We report significant changes in the SRX:DRX in both HFpEF mouse models, with an increased DRX state associated with Alport mice and a stabilized SRX state associated with LDLR/P407 mice. These findings correlate respectively with the hypercontractility and metabolic dysregulation with bradycardia phenotypes.

cell biology↗

bioRxiv2022

Efficacy of a Growth Hormone-Releasing Hormone Agonist in a Murine Model of Cardiometabolic Heart Failure with Preserved Ejection Fraction

Heart failure (HF) with preserved ejection fraction (HFpEF) represents a major unmet medical need owing to its diverse pathophysiology and lack of effective therapies. Potent synthetic, agonists (MR-356 and MR409) of growth hormone-releasing hormone (GHRH) improve the phenotype of models of HF with reduced ejection fraction (HFrEF) and in cardiorenal models of HFpEF. Endogenous GHRH exhibits a broad range of regulatory influences in the cardiovascular (CV) system, aging and plays a role in several cardiometabolic conditions including obesity and diabetes. Whether agonists of GHRH can improve the phenotype of cardiometabolic HFpEF remains untested and unknown. Here we tested the hypothesis that MR-356 can mitigate/reverse the cardiometabolic HFpEF phenotype. C57BL6N mice received a high fat diet (HFD) plus the nitric oxide synthase inhibitor (L-NAME) for 9 weeks. After 5 weeks of HFD+L-NAME regimen, animals were randomized to receive daily injections of MR-356 or placebo during a 4-week period. Control animals received no HFD+L-NAME or agonist treatment. Our results showed the unique potential of MR-356 to treat several HFpEF-like features including cardiac hypertrophy, fibrosis, capillary rarefaction, and pulmonary congestion. MR-356 improved cardiac performance by improving diastolic function, global longitudinal strain (GLS), and exercise capacity. Importantly, the increased expression of cardiac pro-brain natriuretic peptide (pro-BNP), inducible nitric oxide synthase (iNOS) and vascular endothelial growth factor-A (VEGF-A) was restored to normal levels suggesting that MR-356 reduced myocardial stress associated with metabolic inflammation in HFpEF. Thus, agonists of GHRH may be an effective therapeutic strategy for the treatment of cardiometabolic HFpEF phenotype.

physiology↗

bioRxiv2017

Single Cardiac Ventricular Myosins Change Step-Size with Loading

The cardiac myosin motor powers the beating heart by catalyzed ATPase free energy conversion to contractile work. Transgenic mouse models for heart disease express mouse -cardiac myosin heavy chain with human essential light chain (ELC) in wild type (WT), or hypertrophic cardiomyopathy linked mutant forms, A57G or E143K. Mutants modify the ELC actin binding N-terminus or C-terminus regions. Motility and single myosin mechanical characteristics show stark contrasts between the motors related to their average force, power, and displacement while all indicate the ability to down-shift ensemble step-size with increasing load. A57G and E143K consume more ATP than control WT in the presence of actin with A57G upregulating and E143K downregulating power compared with WT. Higher ATP consumption and downregulated power in E143K implies a lower unitary force. Effects on power are consistent with an A57G that impairs the ELC N-terminus actin binding and an E143K that reduces lever-arm rigidity.

biophysics↗