Deranged myofilament phosphorylation and function in experimental heart failure with preserved ejection fraction

Abstract

This patient-mimicking HFpEF model is characterized by titin stiffening through altered isoform composition and phosphorylation, both contributing to increased LV stiffness. Hypophosphorylation of myofilament proteins and increased calcium sensitivity suggest that functional impairment at the sarcomere level may be an early event in HFpEF.

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“…ERK2 presumably reduces the passive tension as well, 141 but this still needs to be shown directly. The PKA effect on passive tension was reported for rat, 136,137 cow, 137 mouse, 146 dog, 117 and human 6,111,112,139 cardiomyocytes ( Figure 7A), the PKG effect for human, 111,140 dog, 117 and rat 125 cardiomyocytes ( Figure 7B). In contrast, PKCα-mediated phosphorylation increased the passive tension of skinned myocytes from mouse and pig heart, an effect amplified by pretreatment with protein phosphatase-1, 144 whereas it did not alter the passive tension of dog cardiomyocytes 117 ( Figure 7C).…”

“…The PKA effect on passive tension was reported for rat, 136,137 cow, 137 mouse, 146 dog, 117 and human 6,111,112,139 cardiomyocytes ( Figure 7A), the PKG effect for human, 111,140 dog, 117 and rat 125 cardiomyocytes ( Figure 7B). In contrast, PKCα-mediated phosphorylation increased the passive tension of skinned myocytes from mouse and pig heart, an effect amplified by pretreatment with protein phosphatase-1, 144 whereas it did not alter the passive tension of dog cardiomyocytes 117 ( Figure 7C). The CaMKIIδ effect on passive tension was seen with skinned mouse cardiomyocytes, 142 and additional evidence for this effect came from mechanical measurements using genetically modified mouse hearts: cardiomyocytes deficient in the 2 CaMKII isoforms, CaMKIIδ and CaMKIIγ (CaMKII-KO), had increased passive tension, whereas those of CaMKIIδ-overexpressing transgenic mice (CaMKII-TG) had reduced passive tension, compared with those of wild-type mice ( Figure 7D).…”

“…An early report demonstrated a reduced N2BA:N2B ratio in a limited number of HFpEF versus HFrEF patient hearts 6 and a follow-up study showed an increased ratio in advanced HFpEF compared with nonfailing donor hearts. 111 In contrast, a hypertensive dog model with diastolic dysfunction revealed a reduced cardiac N2BA:N2B ratio versus healthy dogs 116,117 and slightly decreased N2BA proportions appeared in the spontaneously hypertensive Figure 5. Directions, causes, and consequences of titin-isoform switching in the heart.…”

“…140 Other studies have since demonstrated hypo-phosphorylation of total-titin in human HCM 123 and in animal models of HFpEF. 117,125 A few studies have reported an increased ratio of phospho-N2BA:phospho-N2B in human HF, including HFpEF, aortic stenosis, and HFrEF. 111,112 However, as the N2BA:N2B isoform-expression ratio was also increased in these patient hearts, the proportion of phospho-titin to all-titin (per isoform) may have been similar in the nonfailing and failing hearts.…”

Renin overexpression leads to increased titin-based stiffness contributing to diastolic dysfunction in hypertensive mRen2 rats

“…We found increased phosphorylation at Ser-12742, without changes in the phosphorylation level of Ser-12884 in mRen2 hearts. PEVK Ser-12742 hyperphosphorylation was previously demonstrated in mice with transverse aortic constriction (22), in an old HTN dog model (18), as well as in human HF (17,26). Moreover, a recent translational work implicated the hyperphosphorylation of the very same site (Ser-12742) in human HFpEF (45).…”