Sex dimorphism in the cardiometabolic effects of the smoothelin-like 1 protein deletion in an ageing mouse model

The smoothelin-like 1 (SMTNL1) protein is a regulator of vascular homeostasis, wherein it modulates smooth muscle contraction, myogenic response, endothelial barrier function, and inflammatory responses. Vascular function is known to reciprocally influence cardiac function, with impaired diastole and left ventricular (LV) stiffness causally linked to endothelial dysfunction and coronary microvascular inflammation. SMTNL1, also highly expressed in skeletal muscle, can impact the energy metabolism and insulin sensitivity of female mice during pregnancy. Therefore, I investigated the metabolic and cardiac outcome in a mouse model deficient in SMTNL1 with advancing age. The cardiac function of SMTNL1 global knockout (KO) mice (3-, 12- and 18-month-old, male and female) was assessed by echocardiography and pressure-volume loop, and the metabolic measurements of middle-aged animals (12-month-old, male and female) were carried out in the comprehensive lab animal monitoring system (CLAMS). The cardiac hemodynamic profiling showed that young male SMTNL1 KO mice developed hypertension and diastolic dysfunction as evidenced by increased systolic blood pressure, end diastolic pressure, LV relaxation time constant (tau), and steeper end diastolic pressure-volume relationship. Unlike young males, the 3-month-old female KO mice did not develop diastolic dysfunction. However, ageing elicited progressive impairment of diastolic function in female KO mice with reduced LV diastolic compliance and elevated filling pressures in comparison to their wild-type counterparts, along with a preserved systolic function in all age groups. Furthermore, flow-mediated dilation, an index of endothelial function was impaired in both male and female KO cohorts at 12 months age, the endocrinal equivalent of human menopausal age. Ageing was also associated with altered cardiac morphology and fibrotic levels along with energy imbalance and glucose intolerance with the loss of SMTNL1. Collectively, the study identified pathophysiological effects of SMTNL1 deletion on metabolic, vascular, and diastolic function with increasing age in a sex-dependent manner. The SMTNL1 KO model for the first time recapitulates the sex dimorphic onset of diastolic dysfunction that is central to heart failure with preserved ejection fraction (HFpEF) condition and represents a novel preclinical model with comorbidities to study the etiology of the HFpEF clinical phenotype.

Name thesis:degree_name

Doctor of Philosophy (PhD)

Discipline thesis:degree_discipline

Medicine – Biochemistry and Molecular Biology

Grantor dc:publisher.institution

Cumming School of Medicine

Year dc:date.issued

2023

Author dc:creator

• Murali, Megha

Advisor dc:contributor.advisor

• MacDonald, Justin Anthony

Committee members dc:contributor.committeemember

• Cole, William
• Howlett, Susan
• Thompson, Jennifer
• Patel, Vaibhav
• Childs, Sarah

• HFpEF
• Diastolic dysfunction
• endothelial dysfunction

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

en

DOI

https://dx.doi.org/10.11575/PRISM/dspace/40924

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:1880/116078